Although atovaquone is effective in treating and preventing Pneumocystis pneumonia (PCP), its use is limited by nonlinear absorption and adverse events. The current study was undertaken to examine the activity of encochleated atovaquone (eATQ), a novel lipid-crystal nanoparticle formulation, in a mouse model of PCP. eATQ 100-200 mg was superior to commercially available atovaquone at 14 days in decreasing total Pneumocystis nuclei and asci. eATQ plus anidulafungin reduced nuclei significantly better than commercial atovaquone plus anidulafungin. eATQ is a novel formulation of atovaquone that warrants further evaluation for treatment and prevention of PCP.

BackgroundOnce-weekly isoniazid and rifapentine for 3 months is a treatment option in persons with human immunodeficiency virus and latent tuberculosis infection. This study aimed to examine pharmacokinetic drug-drug interactions between this regimen and dolutegravir, a first-line antiretroviral medication.MethodsThis was a single-center, open-label, fixed-sequence, drug-drug interaction study in healthy volunteers. Subjects received oral dolutegravir 50 mg once daily alone (days 1-4) and concomitantly with once-weekly isoniazid 900 mg, rifapentine 900 mg, and pyridoxine 50 mg (days 5-19). Dolutegravir concentrations were measured on days 4, 14, and 19, and rifapentine, 25-desacetyl-rifapentine, and isoniazid concentrations were measured on day 19. Cytokines and antidrug antibodies to isoniazid and rifapentine were examined at select time points.ResultsThe study was terminated following the development of flu-like syndrome and elevated aminotransferase levels in 2 of 4 subjects after the third isoniazid-rifapentine dose. Markedly elevated levels of interferon-γ, CXCL10, C-reactive protein, and other cytokines were temporally associated with symptoms. Antidrug antibodies were infrequently detected. Dolutegravir area under the curve (AUC) was decreased by 46% (90% confidence interval, 27-110%; P = .13) on day 14. Rifapentine and 25-desacetyl rifapentine levels on day 19 were comparable to reference data, whereas isoniazid AUCs were approximately 67%-92% higher in the subjects who developed toxicities.ConclusionsThe combined use of dolutegravir with once-weekly isoniazid-rifapentine resulted in unexpected and serious toxicities that were mediated by endogenous cytokine release. Additional investigations are necessary to examine the safety and efficacy of coadministering these medications.Clinical Trials RegistrationNCT02771249.

Dabigatran etexilate (DE) is a P-glycoprotein (P-gp) probe substrate, and its active anticoagulant moiety, dabigatran, is a substrate of the multidrug and toxin extrusion protein-1 (MATE-1) transporter. The antiretroviral pharmacokinetic enhancers, ritonavir and cobicistat, inhibit both these transporters. Healthy volunteers received single doses of DE at 150 mg alone, followed by ritonavir at 100 mg or cobicistat at 150 mg daily for 2 weeks. DE was then given 2 h before ritonavir or cobicistat. One week later, DE was given simultaneously with ritonavir or cobicistat. No significant increases in dabigatran pharmacokinetic (PK) exposure or thrombin time (TT) measures were observed with the simultaneous administration of ritonavir. Separated administration of ritonavir resulted in a mean decrease in dabigatran PK exposure of 29% (90% confidence interval [CI], 18 to 40%) but did not significantly change TT measures. However, cobicistat increased dabigatran PK exposure (area under the concentration-versus-time curve from time zero to infinity and maximum plasma concentration) by 127% each (90% CI, 81 to 173% and 59 to 196%, respectively) and increased TT measures (33% for the area-under-the-effect curve from time zero to 24 h [90% CI, 22 to 44%] and 51% for TT at 24 h [90% CI, 22 to 78%]) when given simultaneously with dabigatran. Similar increases were observed when cobicistat was administered separately by 2 h from the administration of dabigatran. In all comparisons, no significant increase in the dabigatran elimination half-life was observed. Therefore, it is likely safe to coadminister ritonavir with DE, while there is a potential need for reduced dosing and prudent clinical monitoring with the coadministration of cobicistat due to the greater net inhibition of intestinal P-gp transport and increased bioavailability. (This study has been registered at ClinicalTrials.gov under identifier NCT01896622.).

Steady‐state population pharmacokinetics of a noncommercial immediate‐release metformin (hydrochloride) drug product were characterized in 28 severely obese children with insulin resistance. The concentration–time profiles with double peaks were well described by a 1‐compartment model with 2 absorption sites. Mean population apparent clearance (CL/F) was 68.1 L/h, and mean apparent volume of distribution (V/F) was 28.8 L. Body weight was a covariate of CL/F and V/F. Estimated glomerular filtration rate was a significant covariate of CL/F (P < .001). SLC22A1 genotype did not significantly affect metformin pharmacokinetics. The response to 6 months of metformin treatment (HbA1c, homeostasis model assessment for insulin resistance, fasting insulin, and glucose changes) did not differ between SLC22A1 wild‐type subjects and carriers of presumably low‐activity SLC22A1 alleles. However, SLC22A1 variant carriers had smaller reductions in percentage of total trunk fat after metformin therapy, although the percentage reduction in trunk fat was small. The median % change in trunk fat was ‐2.20% (‐9.00% to 0.900%) and ‐1.20% (‐2.40% to 7.30%) for the SLC22A1 wild‐type subjects and variant carriers, respectively. Future study is needed to evaluate the effects of SLC22A1 polymorphisms on metformin‐mediated weight reduction in obese children.

Background. The current study was conducted to determine if efavirenz (EFV) or atazanavir/ritonavir (ATV/r)-based combination antiretroviral therapy (cART) impacted steady-state atovaquone plasma concentrations in human immunodeficiency virus (HIV)-infected patients receiving treatment doses of atovaquone.Methods. Thirty HIV-infected volunteers were recruited, 10 taking no cART and 10 each taking cART that included EFV or ATV/r. Subjects were randomly assigned to atovaquone 750 mg twice daily (BID) for 14 days followed by atovaquone 1500 mg BID for 14 days, or vice-versa, with a washout period in between. On day 14 of each phase, blood was sampled for pharmacokinetic studies, and the area under the concentration-time curve (AUCt) and average concentration (C-avg) were calculated and compared using an unpaired t test.Results. Twenty-nine subjects completed both dosing cohorts. Subjects receiving EFV-based cART had 47% and 44% lower atovaquone AUCt than subjects not receiving cART at atovaquone doses of 750 mg BID and 1500 mg BID, respectively (P=.01). Only 5 of 10 subjects receiving EFV-based cART plus atovaquone 750 mg BID had an atovaquone C-avg >15 mu g/mL, which has previously been associated with successful treatment of Pneumocystis jiroveci pneumonia. AUCt and C-avg did not significantly differ for concurrent ATV/r for 750 mg BID or 1500 mg BID when compared to the group not receiving cART. Nine of 10 subjects not receiving cART, 8 of 10 subjects receiving ATV/r, and 2 of 10 subjects receiving EFV in combination with atovaquone 750 mg BID achieved an atovaquone C-avg >18.5 mu g/mL, a concentration that has previously been associated with successful treatment of Toxoplasma encephalitis (TE).Conclusions. These data suggest that the currently recommended dose of atovaquone 750 mg BID for treatment of mild to moderate PCP may not be adequate in patients receiving concurrent EFV. Furthermore, doses lower than the currently recommended dose of 1500 mg BID may achieve plasma concentrations adequate to treat TE in HIV-infected patients not receiving EFV.

HomeCirculationVol. 134, No. 23Antiretroviral Boosting Agent Cobicistat Increases the Pharmacokinetic Exposure and Anticoagulant Effect of Dabigatran in HIV-Negative Healthy Volunteers Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBAntiretroviral Boosting Agent Cobicistat Increases the Pharmacokinetic Exposure and Anticoagulant Effect of Dabigatran in HIV-Negative Healthy Volunteers Lori A. Gordon, PharmD, Parag Kumar, PharmD, Kristina M. Brooks, PharmD, Anela Kellogg, MSN, Maryellen McManus, MPH, Raul M. Alfaro, MS, Khanh Nghiem, MS, Jomy M. George, PharmD, Jay Lozier, MD, PhD, Scott R. Penzak, PharmD and Colleen Hadigan, MD, MPH Lori A. GordonLori A. Gordon From Clinical Pharmacokinetics Research Unit, Clinical Center Pharmacy Department, (L.A.G., R.K., K.M.B., R.M.A., J.M.G., S.R.P.), Clinical Research Center, Clinical Center Department of Laboratory Medicine (K.N., J.L.), National Institute of Allergy and Infectious Diseases (C.H.), National Institutes of Health, Bethesda, MD; Xavier University of Louisiana, College of Pharmacy, New Orleans (L.A.G.); Leidos Biomedical Research, Inc, Frederick, MD (A.K.); Parker Tide Corporation, Washington, DC (M.M.); and University of North Texas System College of Pharmacy, Department of Pharmacotherapy, Fort Worth (S.R.P.). , Parag KumarParag Kumar From Clinical Pharmacokinetics Research Unit, Clinical Center Pharmacy Department, (L.A.G., R.K., K.M.B., R.M.A., J.M.G., S.R.P.), Clinical Research Center, Clinical Center Department of Laboratory Medicine (K.N., J.L.), National Institute of Allergy and Infectious Diseases (C.H.), National Institutes of Health, Bethesda, MD; Xavier University of Louisiana, College of Pharmacy, New Orleans (L.A.G.); Leidos Biomedical Research, Inc, Frederick, MD (A.K.); Parker Tide Corporation, Washington, DC (M.M.); and University of North Texas System College of Pharmacy, Department of Pharmacotherapy, Fort Worth (S.R.P.). , Kristina M. BrooksKristina M. Brooks From Clinical Pharmacokinetics Research Unit, Clinical Center Pharmacy Department, (L.A.G., R.K., K.M.B., R.M.A., J.M.G., S.R.P.), Clinical Research Center, Clinical Center Department of Laboratory Medicine (K.N., J.L.), National Institute of Allergy and Infectious Diseases (C.H.), National Institutes of Health, Bethesda, MD; Xavier University of Louisiana, College of Pharmacy, New Orleans (L.A.G.); Leidos Biomedical Research, Inc, Frederick, MD (A.K.); Parker Tide Corporation, Washington, DC (M.M.); and University of North Texas System College of Pharmacy, Department of Pharmacotherapy, Fort Worth (S.R.P.). , Anela KelloggAnela Kellogg From Clinical Pharmacokinetics Research Unit, Clinical Center Pharmacy Department, (L.A.G., R.K., K.M.B., R.M.A., J.M.G., S.R.P.), Clinical Research Center, Clinical Center Department of Laboratory Medicine (K.N., J.L.), National Institute of Allergy and Infectious Diseases (C.H.), National Institutes of Health, Bethesda, MD; Xavier University of Louisiana, College of Pharmacy, New Orleans (L.A.G.); Leidos Biomedical Research, Inc, Frederick, MD (A.K.); Parker Tide Corporation, Washington, DC (M.M.); and University of North Texas System College of Pharmacy, Department of Pharmacotherapy, Fort Worth (S.R.P.). , Maryellen McManusMaryellen McManus From Clinical Pharmacokinetics Research Unit, Clinical Center Pharmacy Department, (L.A.G., R.K., K.M.B., R.M.A., J.M.G., S.R.P.), Clinical Research Center, Clinical Center Department of Laboratory Medicine (K.N., J.L.), National Institute of Allergy and Infectious Diseases (C.H.), National Institutes of Health, Bethesda, MD; Xavier University of Louisiana, College of Pharmacy, New Orleans (L.A.G.); Leidos Biomedical Research, Inc, Frederick, MD (A.K.); Parker Tide Corporation, Washington, DC (M.M.); and University of North Texas System College of Pharmacy, Department of Pharmacotherapy, Fort Worth (S.R.P.). , Raul M. AlfaroRaul M. Alfaro From Clinical Pharmacokinetics Research Unit, Clinical Center Pharmacy Department, (L.A.G., R.K., K.M.B., R.M.A., J.M.G., S.R.P.), Clinical Research Center, Clinical Center Department of Laboratory Medicine (K.N., J.L.), National Institute of Allergy and Infectious Diseases (C.H.), National Institutes of Health, Bethesda, MD; Xavier University of Louisiana, College of Pharmacy, New Orleans (L.A.G.); Leidos Biomedical Research, Inc, Frederick, MD (A.K.); Parker Tide Corporation, Washington, DC (M.M.); and University of North Texas System College of Pharmacy, Department of Pharmacotherapy, Fort Worth (S.R.P.). , Khanh NghiemKhanh Nghiem From Clinical Pharmacokinetics Research Unit, Clinical Center Pharmacy Department, (L.A.G., R.K., K.M.B., R.M.A., J.M.G., S.R.P.), Clinical Research Center, Clinical Center Department of Laboratory Medicine (K.N., J.L.), National Institute of Allergy and Infectious Diseases (C.H.), National Institutes of Health, Bethesda, MD; Xavier University of Louisiana, College of Pharmacy, New Orleans (L.A.G.); Leidos Biomedical Research, Inc, Frederick, MD (A.K.); Parker Tide Corporation, Washington, DC (M.M.); and University of North Texas System College of Pharmacy, Department of Pharmacotherapy, Fort Worth (S.R.P.). , Jomy M. GeorgeJomy M. George From Clinical Pharmacokinetics Research Unit, Clinical Center Pharmacy Department, (L.A.G., R.K., K.M.B., R.M.A., J.M.G., S.R.P.), Clinical Research Center, Clinical Center Department of Laboratory Medicine (K.N., J.L.), National Institute of Allergy and Infectious Diseases (C.H.), National Institutes of Health, Bethesda, MD; Xavier University of Louisiana, College of Pharmacy, New Orleans (L.A.G.); Leidos Biomedical Research, Inc, Frederick, MD (A.K.); Parker Tide Corporation, Washington, DC (M.M.); and University of North Texas System College of Pharmacy, Department of Pharmacotherapy, Fort Worth (S.R.P.). , Jay LozierJay Lozier From Clinical Pharmacokinetics Research Unit, Clinical Center Pharmacy Department, (L.A.G., R.K., K.M.B., R.M.A., J.M.G., S.R.P.), Clinical Research Center, Clinical Center Department of Laboratory Medicine (K.N., J.L.), National Institute of Allergy and Infectious Diseases (C.H.), National Institutes of Health, Bethesda, MD; Xavier University of Louisiana, College of Pharmacy, New Orleans (L.A.G.); Leidos Biomedical Research, Inc, Frederick, MD (A.K.); Parker Tide Corporation, Washington, DC (M.M.); and University of North Texas System College of Pharmacy, Department of Pharmacotherapy, Fort Worth (S.R.P.). , Scott R. PenzakScott R. Penzak From Clinical Pharmacokinetics Research Unit, Clinical Center Pharmacy Department, (L.A.G., R.K., K.M.B., R.M.A., J.M.G., S.R.P.), Clinical Research Center, Clinical Center Department of Laboratory Medicine (K.N., J.L.), National Institute of Allergy and Infectious Diseases (C.H.), National Institutes of Health, Bethesda, MD; Xavier University of Louisiana, College of Pharmacy, New Orleans (L.A.G.); Leidos Biomedical Research, Inc, Frederick, MD (A.K.); Parker Tide Corporation, Washington, DC (M.M.); and University of North Texas System College of Pharmacy, Department of Pharmacotherapy, Fort Worth (S.R.P.). and Colleen HadiganColleen Hadigan From Clinical Pharmacokinetics Research Unit, Clinical Center Pharmacy Department, (L.A.G., R.K., K.M.B., R.M.A., J.M.G., S.R.P.), Clinical Research Center, Clinical Center Department of Laboratory Medicine (K.N., J.L.), National Institute of Allergy and Infectious Diseases (C.H.), National Institutes of Health, Bethesda, MD; Xavier University of Louisiana, College of Pharmacy, New Orleans (L.A.G.); Leidos Biomedical Research, Inc, Frederick, MD (A.K.); Parker Tide Corporation, Washington, DC (M.M.); and University of North Texas System College of Pharmacy, Department of Pharmacotherapy, Fort Worth (S.R.P.). Originally published6 Dec 2016https://doi.org/10.1161/CIRCULATIONAHA.116.025257Circulation. 2016;134:1909–1911Drug interactions between antiretroviral therapy and anticoagulant medications are of particular concern given that ≈50% of the current HIV population is >50 years of age. Moreover, HIV infection is characterized by a hypercoaguable state and premature immunologic aging, in which thromboembolic events may be as much as 10 times more prevalent than in the general population across all age spectra.1Dabigatran was the first direct oral anticoagulant approved by the US Food & Drug Administration and is the only direct oral anticoagulant with a US Food & Drug Administration -approved specific reversal agent, idarucizumab. Unlike warfarin and many other direct oral anticoagulants, dabigatran is not a substrate, inhibitor, or inducer of cytochrome P450 metabolic enzymes. However, dabigatran is a substrate of Permeability-glycoprotein (P-gp) and renal multidrug and toxin extrusion-1 transporters. Cobicistat is a US Food & Drug Administration -approved antiretroviral-boosting agent that is coformulated with numerous fixed-dose combination antiretroviral products because of its inhibitory effects on cytochrome P450 3A4. Currently, ≈40% of all treatment-naïve patients with HIV in the United States are initiated on a cobicistat-boosted antiretroviral regimen. In addition to cytochrome P450 3A4, cobicistat is also an inhibitor of both P-gp and multidrug and toxin extrusion-1 transporters.2 Thus, this study aimed to determine whether the coadministration of cobicistat increases the systemic exposure and anticoagulant effects of dabigatran and, if so, whether separating administration would circumvent this interaction.This open-label, single-sequence drug interaction study was conducted in healthy HIV-negative volunteers (Clinical Trial Registration: URL: https://www.clinicaltrials.gov, Unique identifier: NCT01896622). All participants gave written informed consent, and the study was approved by the National Institute of Allergy and Infectious Diseases Institutional Review Board. Participants first received a single dose of dabigatran 150 mg alone (Phase 1). After a 5-day washout period, participants then began cobicistat 150 mg daily. After 2 weeks, a second single dose of dabigatran was given 2 hours before cobicistat (Phase 2), and then 1 week later, a third single dose of dabigatran was given simultaneously with cobicistat (Phase 3). After each dabigatran dose, blood was collected serially over 24 hours for pharmacokinetic and thrombin time (TT) analysis (STA-Thrombin assay, Diagnostica Stago, Inc.), including area-under-the-concentration-versus-time curve from time zero to infinity, maximal concentration, area-under-the-TT-effect-versus-time curve, and TT at 24 hours after the dose with Phoenix WinNonlin software (v6.4). P values were calculated by paired Student t tests (Microsoft Excel).Sixteen participants completed all phases of the study, and an additional 2 completed Phases 1 and 2 only. Simultaneous administration of cobicistat (Phase 3) resulted in significant increases in dabigatran pharmacokinetic exposure, with a 127% increase in both the geometric mean area-under-the-concentration-versus-time curve from time zero to infinity and maximal concentration (P<0.001). Although no alterations in drug elimination occurred, significant increases were observed in oral bioavailability (data not shown). Additionally, the anticoagulant effect correspondingly increased, with 33% and 51% increases in the geometric mean area-under-the-TT-effect-versus-time curve and TT at 24 hours after dose, respectively (P<0.001). Separation of administration by 2 hours (Phase 2) minimally mitigated this interaction, with increases in the geometric mean area-under-the-concentration-versus-time curve from zero to infinity, maximal concentration, area-under-the-TT-effect-versus-time curve, and TT at 24 hours after dose of 110%, 99%, 30%, and 46% (P<0.001 for all comparisons), respectively (Figure 1A and 1B). In fact, no significant difference in pharmacokinetic or TT parameters was noted between simultaneous (Phase 3) and separated (Phase 2) administration of cobicistat and dabigatran.Download figureDownload PowerPointFigure. Cobicistat significantly increases dabigratran concentrations and thrombin time response. Mean (±SEM) dabigatran plasma concentration (A) and median (90% confidence interval) thrombin time (B) after administration of dabigatran alone, administration separated by 2 hours, and simultaneously with cobicistat.Previous investigations with intestinal P-gp transporter inhibitors have resulted in increased dabigatran drug exposure and corresponding anticoagulation activity. Härtter et al3 illustrated that this interaction could potentially be obviated by separating administration by 2 hours. In our study, simultaneous cobicistat and dabigatran administration resulted in significant increases in dabigatran exposure and TT measures. However, separated administration by 2 hours was inadequate for circumventing this interaction. Because participants typically experienced maximal dabigatran concentrations 3 to 4 hours after dosing, it is possible that separated administration by ≥4 hours may have circumvented the interaction. However, this strategy may present a considerable challenge for adherence with standard twice-daily dabigatran administration.The true clinical impact on dabigatran's anticoagulant effects may be larger than we measured with the TT assay, STA-Thrombin, which reports a maximum TT value of 120 seconds. Furthermore, this study was conducted in healthy volunteers, as is standard in most drug interaction studies; it is plausible that patients infected with HIV may have altered susceptibility to this interaction. Kis et al4 showed that treatment-experienced patients with HIV have increased P-gp gene expression (3.2-fold) compared with treatment-naïve patients with HIV. Initiation with 110 mg daily and subsequent titration of dose based on dabigatran concentrations was successfully used in a patient infected with HIV; however, this patient was receiving a different antiretroviral boosting agent, ritonavir, which is known to demonstrate mixed P-gp inhibition and induction.2,5Nonetheless, these findings support the need for future investigations conducted in patients receiving concomitant dabigatran and cobicistat to determine whether dose adjustment is clinically indicated and/or effective. It is important to note that all currently available alternative direct oral anticoagulants (rivaroxaban, apixaban, and edoxaban) are expected to interact with cobicistat because of cytochrome P450 3A4 inhibition, leaving subcutaneous enoxaparin or INR-monitored warfarin as the remaining chronic anticoagulant options. Fortunately, the availability of idarucizumab for rapid reversal of anticoagulation may be considered a layer of safety in patients receiving cobicistat-boosted antiretrovirals and dabigatran.Lori A. Gordon, PharmDParag Kumar, PharmDKristina M. Brooks, PharmDAnela Kellogg, MSNMaryellen McManus, MPHRaul M. Alfaro, MSKhanh Nghiem, MSJomy M. George, PharmDJay Lozier, MD, PhDScott R. Penzak, PharmDColleen Hadigan, MD, MPHSources of FundingFunding for this study was provided by the National Institutes of Health Clinical Center Pharmacy Department and the National Institute of Allergy and Infectious Diseases intramural research program.DisclosuresNone.Footnotes*Drs Gordon and Kumar contributed equally.Some of the data contained in this manuscript were previously presented in abstract form at the annual Conference on Retroviruses and Opportunistic Infections in February 2016 in Boston, MA.Circulation is available at http://circ.ahajournals.org.Correspondence to: Parag Kumar, PharmD, Director, Clinical Pharmacokinetics Research Unit, National Institutes of Health, Clinical Center Pharmacy Department, 10 Center Dr, Rm 1C-230G, Bethesda, MD 20892. E-mail [email protected]References1. Saber AA, Aboolian A, LaRaja RD, Baron H, Hanna K. HIV/AIDS and the risk of deep vein thrombosis: a study of 45 patients with lower extremity involvement.Am Surg. 2001; 67:645–647.CrossrefMedlineGoogle Scholar2. Marzolini C, Gibbons S, Khoo S, Back D. Cobicistat versus ritonavir boosting and differences in the drug-drug interaction profiles with co-medications.J Antimicrob Chemother. 2016; 71:1755–1758. doi: 10.1093/jac/dkw032.CrossrefMedlineGoogle Scholar3. Härtter S, Sennewald R, Nehmiz G, Reilly P. Oral bioavailability of dabigatran etexilate (Pradaxa(®)) after co-medication with verapamil in healthy subjects.Br J Clin Pharmacol. 2013; 75:1053–1062. doi: 10.1111/j.1365-2125.2012.04453.x.CrossrefMedlineGoogle Scholar4. Kis O, Sankaran-Walters S, Hoque MT, Walmsley SL, Dandekar S, Bendayan R. HIV-1 alters intestinal expression of drug transporters and metabolic enzymes: implications for antiretroviral drug disposition.Antimicrob Agents Chemother. 2016; 60:2771–2781. doi: 10.1128/AAC.02278-15.CrossrefMedlineGoogle Scholar5. Perram J, Joseph J, Holloway C. Novel oral anticoagulants and HIV: dabigatran use with antiretrovirals.BMJ Case Rep. 2015. doi: 10.1136/bcr-2015–211651.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Seo H, Jen S, Green D, Papadopoulos J and Ahuja T (2021) Direct oral anticoagulants versus warfarin in people living with human immunodeficiency virus, International Journal of STD & AIDS, 10.1177/09564624211031728, 32:13, (1221-1230), Online publication date: 1-Nov-2021. Steffel J, Collins R, Antz M, Cornu P, Desteghe L, Haeusler K, Oldgren J, Reinecke H, Roldan-Schilling V, Rowell N, Sinnaeve P, Vanassche T, Potpara T, Camm A, Heidbüchel H, Lip G, Deneke T, Dagres N, Boriani G, Chao T, Choi E, Hills M, Santos I, Lane D, Atar D, Joung B, Cole O and Field M (2021) 2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation, EP Europace, 10.1093/europace/euab065, 23:10, (1612-1676), Online publication date: 9-Oct-2021. Burger D, Calmy A and Marzolini C (2020) Cobicistat: A case of mislabelled drug‐drug interaction risk?, British Journal of Clinical Pharmacology, 10.1111/bcp.14262, 86:5, (834-836), Online publication date: 1-May-2020. Cattaneo D, Cossu M and Rizzardini G (2019) Pharmacokinetic drug evaluation of ritonavir (versus cobicistat) as adjunctive therapy in the treatment of HIV, Expert Opinion on Drug Metabolism & Toxicology, 10.1080/17425255.2019.1685495, 15:11, (927-935), Online publication date: 2-Nov-2019. Nisly S and Stevens B (2019) Ritonavir- or cobicistat-boosted antiretroviral therapy and direct oral anticoagulants: A case for apixaban, International Journal of STD & AIDS, 10.1177/0956462419832099, 30:7, (718-722), Online publication date: 1-Jun-2019. Herink M, Zhuo Y, Williams C and DeLoughery T (2019) Clinical Management of Pharmacokinetic Drug Interactions with Direct Oral Anticoagulants (DOACs), Drugs, 10.1007/s40265-019-01183-0, 79:15, (1625-1634), Online publication date: 1-Oct-2019. Huo X, Meng Q, Wang C, Zhu Y, Liu Z, Ma X, Ma X, Peng J, Sun H and Liu K (2019) Cilastatin protects against imipenem-induced nephrotoxicity via inhibition of renal organic anion transporters (OATs), Acta Pharmaceutica Sinica B, 10.1016/j.apsb.2019.02.005, 9:5, (986-996), Online publication date: 1-Sep-2019. Kakadiya P, Higginson R and Fulco P (2018) Ritonavir-Boosted Protease Inhibitors but Not Cobicistat Appear Safe in HIV-Positive Patients Ingesting Dabigatran, Antimicrobial Agents and Chemotherapy, 10.1128/AAC.02275-17, 62:2, Online publication date: 1-Feb-2018. Gelosa P, Castiglioni L, Tenconi M, Baldessin L, Racagni G, Corsini A and Bellosta S (2018) Pharmacokinetic drug interactions of the non-vitamin K antagonist oral anticoagulants (NOACs), Pharmacological Research, 10.1016/j.phrs.2018.07.016, 135, (60-79), Online publication date: 1-Sep-2018. Yoong D, Naccarato M and Gough K (2017) Extensive Bruising and Elevated Rivaroxaban Plasma Concentration in a Patient Receiving Cobicistat-Boosted Elvitegravir, Annals of Pharmacotherapy, 10.1177/1060028017702677, 51:8, (713-714), Online publication date: 1-Aug-2017. Durham S, Badowski M, Liedtke M, Rathbun R and Pecora Fulco P (2017) Acute Care Management of the HIV-Infected Patient: A Report from the HIV Practice and Research Network of the American College of Clinical Pharmacy, Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 10.1002/phar.1921, 37:5, (611-629), Online publication date: 1-May-2017. Sebaaly J and Kelley D (2017) Comment: Extensive Bruising and Elevated Rivaroxaban Plasma Concentration in a Patient Receiving Cobicistat-Boosted Elvitegravir, Annals of Pharmacotherapy, 10.1177/1060028017717738, 51:10, (929-930), Online publication date: 1-Oct-2017. Chary A, Nguyen N, Maiton K and Holodniy M (2017) A review of drug-drug interactions in older HIV-infected patients, Expert Review of Clinical Pharmacology, 10.1080/17512433.2017.1377610, 10:12, (1329-1352), Online publication date: 2-Dec-2017. Kumar P, Gordon L, Brooks K, George J, Kellogg A, McManus M, Alfaro R, Nghiem K, Lozier J, Hadigan C and Penzak S (2017) Differential Influence of the Antiretroviral Pharmacokinetic Enhancers Ritonavir and Cobicistat on Intestinal P-Glycoprotein Transport and the Pharmacokinetic/Pharmacodynamic Disposition of Dabigatran, Antimicrobial Agents and Chemotherapy, 10.1128/AAC.01201-17, 61:11, Online publication date: 1-Nov-2017. Stöllberger C (2017) Drug interactions with new oral anticoagulants in elderly patients, Expert Review of Clinical Pharmacology, 10.1080/17512433.2017.1370369, 10:11, (1191-1202), Online publication date: 2-Nov-2017. December 6, 2016Vol 134, Issue 23 Advertisement Article InformationMetrics © 2016 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.116.025257PMID: 27920076 Originally publishedDecember 6, 2016 Keywordsantiretroviralthrombin timepharmacokineticsanticoagulantspharmacodynamicsdrug-drug interactiondabigatrancobicistatPDF download Advertisement SubjectsAnticoagulantsAtrial FibrillationEmbolismPharmacologyThrombosis

Study ObjectiveBecause we previously observed a significant 41% reduction in gemfibrozil exposure after 2weeks of lopinavir-ritonavir administration, we sought to determine the influence of lopinavir-ritonavir and ritonavir alone on the pharmacokinetics of fenofibric acid, an alternative to gemfibrozil for the treatment of elevated triglyceride levels.DesignOpen-label, single-sequence pharmacokinetic study.SettingClinical Research Center at the National Institutes of Health.SubjectsThirteen healthy adult volunteers.InterventionSubjects received a single oral dose of fenofibrate 145mg during three study phases: before ritonavir administration, after 2weeks of administration of ritonavir 100mg twice/day, and after 2weeks of administration of lopinavir 400mg-ritonavir 100mg twice/day.Measurements and Main ResultsSerial blood samples were collected over 120hours for determination of fenofibric acid concentrations. Fenofibric acid pharmacokinetic parameter values were compared before and after concomitant ritonavir or lopinavir-ritonavir administration. The geometric mean ratios (90% confidence intervals) for fenofibric acid area under the plasma concentration-time curve were 0.89 (0.77-1.01) after 14days of ritonavir alone compared with baseline (p>0.05) and 0.87 (0.69-1.05) after 14days of lopinavir-ritonavir compared with baseline (p>0.05). Study drugs were generally well tolerated; all adverse events were mild or moderate, transient, and resolved without intervention.ConclusionIn contrast to a significant interaction between gemfibrozil and lopinavir-ritonavir, neither lopinavir-ritonavir nor ritonavir alone altered the pharmacokinetics of fenofibric acid in healthy volunteers. These data suggest that fenofibrate remains an important option in human immunodeficiency virus-infected patients receiving common ritonavir-boosted therapy.

STUDY OBJECTIVE Panax ginseng has been shown in preclinical studies to modulate cytochrome P450 enzymes involved in the metabolism of HIV protease inhibitors. Therefore, the purpose of this study was to determine the influence of P. ginseng on the pharmacokinetics of the HIV protease inhibitor combination lopinavir-ritonavir (LPV-r) in healthy volunteers.DESIGN Single-sequence, open-label, single-center pharmacokinetic investigation.SETTING Government health care facility.SUBJECTS Twelve healthy human volunteers.MEASUREMENTS AND MAIN RESULTS Twelve healthy volunteers received LPV-r (400-100 mg) twice/day for 29.5 days. On day 15 of LPV-r administration, serial blood samples were collected over 12 hours for determination of lopinavir and ritonavir concentrations. On study day 16, subjects began taking P. ginseng 500 mg twice/day, which they continued for 2 weeks in combination with LPV-r. On day 30 of LPV-r administration, serial blood samples were again collected over 12 hours for determination of lopinavir and ritonavir concentrations. Lopinavir and ritonavir pharmacokinetic parameter values were determined using noncompartmental methods, and preadministration and postadministration ginseng values were compared using a Student t test, where p<0.05 was accepted as statistically significant.CONCLUSION Neither lopinavir nor ritonavir steady-state pharmacokinetics were altered by 2 weeks of P. ginseng administration to healthy human volunteers. Thus, a clinically significant interaction between P. ginseng and LPV-r is unlikely to occur in HIV-infected patients who choose to take these agents concurrently. It is also unlikely that P. ginseng will interact with other ritonavir-boosted protease inhibitor combinations, although confirmatory data are necessary.

Objective: To identify an alternative inhaled corticosteroid to fluticasone propionate that can be safely coadministered with HIV protease inhibitors, the safety and pharmacokinetics of beclomethasone dipropionate (BDP) and its active metabolite, beclomethasone 17-monopropionate (17-BMP), in combination with ritonavir (RTV) and darunavir/ritonavir (DRV/r) were assessed. Design: Open-label, prospective, randomized pharmacokinetic and pharmacodynamic study in healthy volunteers.Methods: Thirty healthy volunteers received inhaled 160 mu g bid BDP for 14 days and were then randomized (1: 1: 1) into 3 groups: group 1 (control) remained on BDP alone for 28 days, group 2 received 100 mg bid BDP + RTV for 28 days, and group 3 received 600/100 mg bid BDP + DRV/r for 28 days. Pharmacokinetic sampling for 17-BMP was performed on days 14 and 28, and pharmacokinetic parameter values were compared within patients and between groups. Cortisol stimulation testing was also performed on days 1, 14, 28, and 42 and compared within and between groups.Results: Geometric mean ratios (day 28: day 14) (90% confidence interval) for 17-BMP area under the concentration-time curve in groups 1, 2, and 3, respectively, were 0.93 (0.81 to 1.06, P = 0.27), 2.08 (1.52 to 2.65, P = 0.006), and 0.89 (0.68 to 1.09, P = 0.61). There were no significant reductions in serum cortisol levels within or between groups (P > 0.05).Conclusions: DRV/r did not increase 17-BMP exposure, whereas RTV alone produced a statistically significant but clinically inconsequential 2-fold increase in 17-BMP exposure. Adrenal suppression was not observed in any of the study groups. These data suggest that BDP can be safely coadministered with DRV/r and likely other RTV-boosted protease inhibitors.

A number of herbal preparations have been shown to interact with prescription medications secondary to modulation of cytochrome P450 (CYP) and/or P‐glycoprotein (P‐gp). The purpose of this study was to determine the influence of Panax ginseng on CYP3A and P‐gp function using the probe substrates midazolam and fexofenadine, respectively. Twelve healthy participants (8 men) completed this open‐label, single‐sequence pharmacokinetic study. Healthy volunteers received single oral doses of midazolam 8 mg and fexofenadine 120 mg, before and after 28 days of P ginseng 500 mg twice daily. Midazolam and fexofenadine pharmacokinetic parameter values were calculated and compared before and after P ginseng administration. Geometric mean ratios (postginseng/preginseng) for midazolam area under the concentration‐time curve from zero to infinity (AUC0‐∞), half‐life (t1/2), and maximum concentration (Cmax) were significantly reduced at 0.66 (0.55–0.78), 0.71 (0.53–0.90), and 0.74 (0.56–0.93), respectively. Conversely, fexofenadine pharmacokinetics were unaltered by P ginseng administration. Based on these results, P ginseng appeared to induce CYP3A activity in the liver and possibly the gastrointestinal tract. Patients taking P ginseng in combination with CYP3A substrates with narrow therapeutic ranges should be monitored closely for adequate therapeutic response to the substrate medication.

Study Objective. To determine the influence of Echinacea purpurea on the pharmacokinetics of lopinavir‐ritonavir and on cytochrome P450 (CYP)3A and P‐glycoprotein activity by using the probe substrates midazolam and fexofenadine, respectively.Design. Open‐label, single‐sequence pharmacokinetic study.Setting. Outpatient clinic in a federal government research center.Subjects. Thirteen healthy volunteers (eight men, five women).Intervention. Subjects received lopinavir 400 mg‐ritonavir 100 mg twice/day with meals for 29.5 days. On day 16, subjects received E. purpurea 500 mg 3 times/day for 28 days: 14 days in combination with lopinavir‐ritonavir and 14 days ofE. purpureaalone. In order to assess CYP3A and P‐glycoprotein activity, subjects received single oral doses of midazolam 8mg and fexofenadine 120 mg, respectively, before and after the 28 days of E. purpurea.Measurements and Main Results. On days 15 and 30 of lopinavir‐ritonavir administration (before and after E. purpurea administration, respectively), serial blood samples were collected over 12 hours to determine lopinavir and ritonavir concentrations and subsequent pharmacokinetic parameters by using noncompartmental methods. Neither lopinavir nor ritonavir pharmacokinetics were significantly altered by 14 days of E. purpurea coadministration. The post‐echinacea:pre‐echinacea geometric mean ratios (GMRs) for lopinavir area under the concentration‐time curve (AUC) from 0–12 hours and for maximum concentration were 0.96 (90% confidence interval [CI] 0.83–1.10, p=0.82) and 1.00 (90% CI 0.88–1.12, p=0.72), respectively. Conversely, GMRs for midazolam AUC from time zero extrapolated to infinity and oral clearance were 0.73 (90% CI 0.61–0.85, p=0.008) and 1.37 (90% CI 1.10–1.63, p=0.02), respectively. Fexofenadine pharmacokinetics did not significantly differ before and after E. purpurea administration (p>0.05).Conclusion. Echinacea purpureainduced CYP3A activity but did not alter lopinavir concentrations, most likely duetothe presenceofthe potent CYP3A inhibitor, ritonavir. Echinacea purpureais unlikely to alter the pharmacokinetics of ritonavir‐boosted protease inhibitors but may cause modest decreases in plasma concentrations of other CYP3A substrates.

OBJECTIVE:The objective of this study was to determine the influence of a 2-week course of lopinavir-ritonavir on the pharmacokinetics of the triglyceride-lowering agent, gemfibrozil. METHODS:The study was conducted as an open label, single-sequence pharmacokinetic study in healthy human volunteers. Gemfibrozil pharmacokinetic parameter values were compared using a Student t test after a single 600-mg dose was administered to healthy volunteers before and after 2 weeks of lopinavir-ritonavir (400/100 mg) twice daily. RESULTS:Fifteen healthy volunteers (eight males) completed the study. All study drugs were generally well tolerated and no subjects withdrew participation. The geometric mean ratio (90% confidence interval) for gemfibrozil area under the plasma concentration-time curve after 14 days of lopinavir-ritonavir compared with baseline was 0.59 (0.52, 0.67) (P < 0.001). All 15 study subjects experienced a reduction in gemfibrozil area under the plasma concentration-time curve after lopinavir-ritonavir (range, -6% to -74%). The geometric mean ratios for gemfibrozil apparent oral clearance and maximum concentration were 1.69 (1.41, 1.97) and 0.67 (0.49, 0.86) after 14 days of lopinavir-ritonavir versus baseline, respectively (P < 0.0001 and 0.01, respectively). Gemfibrozil elimination half-life did not change after lopinavir-ritonavir administration (P = 0.60). CONCLUSION:Lopinavir-ritonavir significantly reduced the systemic exposure of gemfibrozil by reducing gemfibrozil absorption. Clinicians treating HIV-infected patients with hypertriglyceridemia should be aware of this drug interaction.

Background: Corticosteroids are cytochrome P450 3A4 substrates, which have been associated with toxicities in patients receiving cytochrome P450 3A4 inhibitors such as human immunodeficiency virus protease inhibitors. In a study in healthy volunteers, ritonavir significantly increased prednisolone exposure.Methods: We investigated the influence of antiretroviral (ARV) medications on prednisolone pharmacokinetics in 3 groups of 10 human immunodeficiency virus-infected subjects. One group received lopinavir/ritonavir, and another efavirenz, as part of their ARV regimen; a third group did not receive ARV medications. Each subject received a single 20-mg prednisone dose followed by serial blood sampling for prednisolone. Prednisolone pharmacokinetics were compared among the groups.Results: Area under the concentration-time curve was significantly lower in efavirenz recipients versus subjects receiving lopinavir/ ritonavir (geometric mean ratio = 0.60, P = 0.01). Average prednisolone area under the concentration-time curve was higher in subjects taking lopinavir/ritonavir versus subjects not on ARVs; however, this difference was not significant (P > 0.05).Conclusions: These data indicate that prednisolone concentrations may fluctuate widely when human immunodeficiency virus-positive individuals established on efavirenz therapy change to lopinavir/ ritonavir or vice versa.

OBJECTIVE:Animal and in vitro data suggest that Ginkgo biloba extract (GBE) may modulate CYP3A4 activity. As such, GBE may alter the exposure of HIV protease inhibitors metabolized by CYP3A4. It is also possible that GBE could alter protease inhibitor pharmacokinetics (PK) secondary to modulation of P-glycoprotein (P-gp). The primary objective of the study was to evaluate the effect of GBE on the exposure of lopinavir in healthy volunteers administered lopinavir/ritonavir. Secondary objectives were to compare ritonavir exposure pre- and post-GBE, and assess the effect of GBE on single doses of probe drugs midazolam and fexofenadine.METHODS:This open-label study evaluated the effect of 2 weeks of standardized GBE administration on the steady-state exposure of lopinavir and ritonavir in 14 healthy volunteers administered lopinavir/ritonavir to steady-state. In addition, single oral doses of probe drugs midazolam and fexofenadine were administered prior to and after 4 weeks of GBE (following washout of lopinavir/ritonavir) to assess the influence of GBE on CYP3A and P-gp activity, respectively.RESULTS:Lopinavir, ritonavir and fexofenadine exposures were not significantly affected by GBE administration. However, GBE decreased midazolam AUC(0-infinity) and C(max) by 34% (p = 0.03) and 31% (p = 0.03), respectively, relative to baseline. In general, lopinavir/ritonavir and GBE were well tolerated. Abnormal laboratory results included mild elevations in hepatic enzymes, cholesterol and triglycerides, and mild-to-moderate increases in total bilirubin.CONCLUSIONS:Our results suggest that GBE induces CYP3A metabolism, as assessed by a decrease in midazolam concentrations. However, there was no change in the exposure of lopinavir, likely due to ritonavir's potent inhibition of CYP3A4. Thus, GBE appears unlikely to reduce the exposure of ritonavir-boosted protease inhibitors, while concentrations of unboosted protease inhibitors may be affected. Limitations to our study include the single sequence design and the evaluation of a ritonavir-boosted protease inhibitor exclusively.

Objective: To characterize the effect of efavirenz on bupropion hydroxylation as a marker of cytochrome P450 (CYP) 2B6 activity in healthy subjects. Methods: Thirteen subjects received a single oral dose of bupropion SR 150 mg before and after 2 weeks of efavirenz administration for comparison of bupropion and hydroxybupropion pharmacokinetics. Efavirenz plasma concentrations were also assessed. Subjects were genotyped for CYP2B6 (G516T, C1459T, and A785G), CYP3A4 (A-392G), CYP3A5 (A6986G), and multidrug resistance protein 1 (C3435T). Results: The area under the concentration vs. time curve ratio of hydroxybupropion:bupropion increased 2.3-fold after efavirenz administration (P = 0.0001). Bupropion area under the concentration vs. time curve and Cmax decreased by 55% and 34%, respectively (P < 0.002). None of the CYP2B6 or CYP3A genotypes evaluated were associated with a difference in bupropion or efavirenz clearance. The 2 individuals homozygous for multidrug resistance protein 1 3435-T/T had 2.5- and 1.8-fold greater bupropion and efavirenz clearance, respectively, relative to C/C and C/T individuals (P < 0.05). Conclusions: Our results confirm that efavirenz induces CYP2B6 enzyme activity in vivo, as demonstrated by an increase in bupropion hydroxylation after 2 weeks of efavirenz administration.

Midazolam is a common probe used to predict CYP3A activity, but multiple blood samples are necessary to determine midazolam's area under the concentration‐time curve (AUC). As such, single sampling strategies have been examined. The purpose of this study was to assess the ability of single midazolam concentrations to predict midazolam AUC in the presence and absence of CYP3A modulation by Ginkgo biloba extract (GBE). Subjects received oral midazolam 8 mg before and after 28 days of GBE administration. Postdose blood samples were collected during both study periods and midazolam AUC determined. Linear regression was used to generate measures of predictive performance for each midazolam concentration. The geometric mean ratio (90% confidence intervals) of midazolam AUC 0‐∞ post‐GBE/AUC 0‐∞ pre‐GBE was 0.66 (0.49–0.84) ( P = .03). Before and after GBE administration, optimal midazolam sampling times were identified at 3.5 to 5 hours and 2 to 3 hours, respectively. Single midazolam concentrations between 2 and 5 hours correctly predicted the reduction in midazolam AUC following GBE exposure, but confidence intervals were generally wide. Intersubject variability in CYP3A activity (either inherent or from drug administration) alters the prediction of optimal midazolam sampling times; therefore, midazolam AUC is preferred for assessing CYP3A activity in drug‐drug interaction studies.

Valganciclovir is commonly used for cytomegalovirus (CMV) prophylaxis in renal transplant patients. A fixed dose of 900 mg daily is typically recommended, however, there has never been a formal pharmacokinetic study comparing various doses in renal transplant patients. We therefore compared the pharmacokinetic characteristics of intravenous ganciclovir (IV GCV) and oral ganciclovir (GCV) with two different doses of valganciclovir (VGCV) in an open‐label crossover study. Ten adult kidney recipients participated in a four‐phase crossover treatment schedule of IV GCV (2.5 mg/kg every 12 h), VGCV (900 mg daily), VGCV (450 mg daily) and oral GCV (1000 mg Q8 H). IV GCV and oral VGCV 900 mg daily achieved similar values for AUC0–24 (median 60.63 vs. 62.86 μg/h/mL). Oral VGCV 450 mg achieved comparable AUC0–24 values as oral GCV 1000 mg Q8 H (median AUC0–24 35.9 vs. 29.04 μg/h/mL). Oral VGCV 900 mg daily provided systemic GCV exposure similar to IV GCV and confirms PV 16 000 study results. Further, VGCV 450 mg daily provided comparable systemic exposure versus oral GCV. Due to its favorable pharmacokinetic profile, data herein suggest that VGCV can be used in the early post‐kidney transplant period, and that 450 mg daily provides ample drug exposure for effective CMV prophylaxis in kidney transplant patients.

Objective Polymorphisms in the cytochrome P450 (CYP) 2B6 gene have been shown to influence nevirapine plasma concentrations in HIV-infected European Caucasians. Although nevirapine is used extensively in Africa, the influence of CYP2B6 genotype on nevirapine exposure has not been assessed in this population. We aimed to determine the influence of CYP2B6 genotype at position 516 on nevirapine trough concentrations in HIV-infected patients in Kampala, Uganda. Additional polymorphisms in the CYP and multidrug resistance protein-1 (MDR-1) genes were also assessed for their impact on nevirapine concentrations.Methods The following genotypes were determined in all subjects using polymerase chain reaction-restriction fragment length polymorphism: CYP2B6 G516T, MDR-1 C3435T and G2677T, CYP3A4(*)1B and CYP3A5(*)3. Nevirapine plasma concentrations were determined using high-performance liquid chromatography in 23 HIV-infected patients who were generally healthy and had been taking nevirapine 200 mg twice daily for at least 14 days. Analysis of variance with post hoc testing was used to compare nevirapine concentrations among CYP2B6 genotype groups.Results The median nevirapine trough concentration in individuals homozygous for the variant allele (TT) was 7607 ng/mL vs 4181 and 5559 ng/mL for GG and GT individuals, respectively (GG vs TT median ratio=1.82; P=0.011). The mean ratio for TT vs GG individuals (95% confidence interval) was 1.51 (1.18, 1.84). No associations were observed between the other polymorphisms studied and nevirapine concentrations.Conclusions CYP2B6 G516T significantly influenced nevirapine trough concentrations in HIV-infected patients in Uganda. Additional studies in larger patient populations are necessary to further define the potential clinical impact of these preliminary findings.

ABSTRACT We investigated the compartmentalized intrapulmonary pharmacokinetics of amphotericin B and its lipid formulations in healthy rabbits. Cohorts of three to seven noninfected, catheterized rabbits received 1 mg of amphotericin B deoxycholate (DAMB) per kg of body weight or 5 mg of either amphotericin B colloidal dispersion (ABCD), amphotericin B lipid complex (ABLC), or liposomal amphotericin B (LAMB) per kg once daily for a total of 8 days. Following sparse serial plasma sampling, rabbits were sacrificed 24 h after the last dose, and epithelial lining fluid (ELF), pulmonary alveolar macrophages (PAM), and lung tissue were obtained. Pharmacokinetic parameters in plasma were derived by model-independent techniques, and concentrations in ELF and PAM were calculated based on the urea dilution method and macrophage cell volume, respectively. Mean amphotericin B concentrations ± standard deviations (SD) in lung tissue and PAM were highest in ABLC-treated animals, exceeding concurrent plasma levels by 70- and 375-fold, respectively (in lung tissue, 16.24 ± 1.62 versus 2.71 ± 1.22, 6.29 ± 1.17, and 6.32 ± 0.57 μg/g for DAMB-, ABCD-, and LAMB-treated animals, respectively [ P = 0.0029]; in PAM, 89.1 ± 37.0 versus 8.92 ± 2.89, 5.43 ± 1.75, and 7.52 ± 2.50 μg/ml for DAMB-, ABCD-, and LAMB-treated animals, respectively [ P = 0.0246]). By comparison, drug concentrations in ELF were much lower than those achieved in lung tissue and PAM. Among the different cohorts, the highest ELF concentrations were found in LAMB-treated animals (2.28 ± 1.43 versus 0.44 ± 0.13, 0.68 ± 0.27, and 0.90 ± 0.28 μg/ml in DAMB-, ABCD-, and ABLC-treated animals, respectively [ P = 0.0070]). In conclusion, amphotericin B and its lipid formulations displayed strikingly different patterns of disposition in lungs 24 h after dosing. Whereas the disposition of ABCD was overall not fundamentally different from that of DAMB, ABLC showed prominent accumulation in lung tissue and PAM, while LAMB achieved the highest concentrations in ELF.

Aims To examine the influence of sex on steady-state saquinavir pharmacokinetics in HIV-seronegative volunteers administered saquinavir without a concomitant protease inhibitor.Methods Thirty-eight healthy volunteers (14 female) received saquinavir soft-gel capsules 1200 mg three times daily for 3 days to achieve steady-state conditions. Following administration of the 10th dose, blood was collected serially over 8 h for measurement of saquinavir plasma concentrations. Saquinavir pharmacokinetic parameter values were determined using noncompartmental methods and compared between males and females. CYP3A phenotype (using oral midazolam) and MDR-1 genotypes at positions 3435 and 2677 were determined for all subjects in order to characterize possible mechanisms for any observed sex-related differences.Results There was no significant difference in saquinavir AUC(0-8) or any other pharmacokinetic parameter value between the sexes. These findings persisted after mathematically correcting for total body weight. The mean weight-normalized AUC(0-8) was 29.9 (95% confidence interval 15.5, 44.3) and 29.8 (18.6, 40.9) ng h(-1) ml(-1) kg(-1) for males and females, respectively. No significant difference in CYP3A phenotype was observed between the groups; likewise, the distribution of MDR-1 genotypes was similar for males and females.Conclusion In contrast to previous study findings, results from this investigation showed no difference in saquinavir pharmacokinetics between males and females. The discrepancy between our findings and those previously reported may be explained by the fact that we evaluated HIV-seronegative volunteers and administered saquinavir in the absence of concomitant protease inhibitors such as ritonavir. Caution must be exercised when extrapolating pharmacokinetic data from healthy volunteer studies (including sex-based pharmacokinetic differences) to HIV-infected populations or to patients receiving additional concurrent medications.