Placement of image-guided tunneled and non-tunneled large-bore central venous catheters (CVCs) are common procedures in interventional radiology. Although leukopenia and/or thrombocytopenia are common at the time of placement, the roles these factors may have in subsequent catheter-related infection have yet to be investigated. A single-institution retrospective review was performed in patients who underwent CVC placement in interventional radiology between 11/2018-6/2019. The electronic medical record was used to obtain demographics, procedure details, pre-placement laboratory values, and the subsequent 90-day follow-up. A total of 178 tunneled and non-tunneled CVCs met inclusion criteria during this time period. White blood cell (WBC) and platelet counts were found to be significant risk factors for subsequent infection. Administration of pre-procedure antibiotics was not found to be a significant factor for subsequent infection (p = 0.075). Leukopenia and thrombocytopenia at the time of CVC placement are both risk factors of line infection for tunneled large-bore CVCs. This should lead to the consideration of using a non-tunneled CVC when clinically feasible, or the delayed placement of these catheters until counts recover.

In this study, we aimed to evaluate the utility of endogenous 1β-hydroxy-deoxycholic acid/total deoxycholic acid ratio (1β-OH-DCA/ToDCA) in spot urine as a surrogate marker of cytochrome P450 3A (CYP3A) activity in the assessment inhibition-based drug–drug interactions in healthy volunteers. This was accomplished through an open-label, three-treatment parallel-arm study in healthy male volunteers from Zimbabwe. Each group received itraconazole (ITZ; 100 mg once daily; n = 10), fluconazole (FKZ; 50 mg once daily; n = 9), or alprazolam (APZ; 1 mg once daily; n = 8) orally. Midazolam (MDZ), dosed orally and intravenously, was used as a comparator to validate the exploratory measures of CYP3A activity and the effects of known inhibitors. Urinary metabolic ratios of 1β-OH-DCA/ToDCA before and after CYP3A inhibitor treatment showed a similar magnitude of inhibitory effects of the three treatments as that measured by oral MDZ clearance. The maximum inhibition effect of a 75% reduction in the 1β-OH-DCA/ToDCA ratio compared to the baseline was achieved in the ITZ group following six once-daily doses of 100 mg. The correlations of the two markers for CYP3A inhibitor treatment were significant (rs = 0.53, p < 0.01). The half-life of urinary endogenous 1β-OH-DCA/ToDCA was estimated as four days. These results suggested that 1β-OH-DCA/ToDCA in spot urine is a promising convenient, non-invasive, sensitive, and relatively quickly responsive endogenous biomarker that can be used for CYP3A inhibition-based drug–drug interaction in clinical studies.

The author declared no competing interests for this work.

Efavirenz-based combination antiretroviral therapy (cART) is associated with neuropsychiatric adverse events. We investigated the time to onset, duration, clinical implications, impact of pharmacogenetic variations, and anti-tuberculosis co-treatment on efavirenz-associated neuropsychiatric manifestations.

The impact of anti-tuberculosis co-treatment on efavirenz (EFV) exposure is still uncertain as contradictory reports exist, and the relevance of CYP2B6*6 genetic polymorphism on efavirenz clearance while on-and-off anti-tuberculosis co-treatment is not well investigated. We investigated the determinants of long-term efavirenz pharmacokinetics by enrolling HIV (n = 20) and HIV/Tuberculosis (n = 36) subjects undergoing efavirenz and efavirenz/rifampicin co-treatment respectively. Pharmacokinetic samplings were done 16 weeks after initiation of efavirenz-based anti-retroviral therapy and eight weeks after completion of rifampicin-based anti-tuberculosis treatment. Population pharmacokinetic modeling was used to characterize variabilities and covariates of efavirenz pharmacokinetic parameters. CYP2B6*6 genetic polymorphism but not rifampicin co-treatment was the statistically significant covariate. The estimated typical efavirenz clearance in the HIV only subjects with the CYP2B6*1/*1 genotype was 23.6 L/h/70 kg, while it was 38% and 69% lower in subjects with the CYP2B6*1/*6 and *6/*6 genotypes, respectively. Among subjects with the same CYP2B6 genotypes, efavirenz clearances were comparable between HIV and HIV/Tuberculosis subjects. Typical efavirenz clearances before and after completion of anti-tuberculosis therapy were comparable. In conclusion, after 16 weeks of treatment, efavirenz clearance is comparable between HIV and HIV/Tuberculosis patients with the same CYP2B6 genotype. CYP2B6 genotyping but not anti-tuberculosis co-treatment should guide efavirenz dosing to optimize treatment outcomes.

Recent studies indicate that inflammation may also affect CYP3A4 activity. Associations of CYP3A4-mediated metabolism of quinine, with inflammatory biomarkers were investigated in patients undergoing maintenance hemodialysis (HD).

N-acetyltransferase 2 (NAT2) metabolize several drugs including isoniazid. We investigated the effect of genotype, geographical difference, and smoking habit on NAT2 phenotype in Ethiopians. Genotyping for NAT2 191G > A, 341 T > C, 590G > A, and 857G > A was performed in 163 unrelated healthy Ethiopians (85 living in Ethiopia and 78 living in Sweden). The NAT2 phenotype was determined using caffeine as a probe and log AFMU/(AFMU + 1X + 1 U) urinary metabolic ratio (MR) as an index. The frequencies of NAT2*4, *5, *6, *7, and *14 haplotypes were 14.1, 48.5, 30.1, 5.5, and 1.8%, respectively. The frequencies of rapid (NAT2*4/*4), intermediate (heterozygous *4), and slow (no *4 allele) acetylator genotypes were 1.8, 24.6, and 73.6%, respectively. The distribution NAT2 MR was bimodal with 70% being phenotypically slow acetylators. NAT2 genotype (p < 0.0001) and country of residence (p = 0.004) independently predicted NAT2 phenotype. Controlling for the effect of genotype, ethnic Ethiopians living in Ethiopia had significantly higher NAT2 MR than those living in Sweden (p = 0.006). NAT2 genotype-phenotype concordance rate was 75%. Distinct country-of-residence-based genotype-phenotype discordance was observed. The proportion of phenotypically determined rapid acetylators was significantly higher and slow acetylators was lower in Ethiopians living in Ethiopia (39% rapid, 61% slow) than in Sweden (20% rapid, 80% slow). Sex and smoking had no significant effect on NAT2 MR. We report a high prevalence of NAT 2 slow acetylators in Ethiopians and a conditional NAT2 genotype-phenotype discordance implicating a partial phenotype conversion and metabolic adaptation. Gene-environment interactions regulate NAT2 phenotype.

Behçet's disease (BD) is a systemic autoimmune disorder. Cytochrome P450 enzymes (CYPs) are responsible for various drug metabolism reactions as well as those of endogenous substances which may be associated with autoimmune disease susceptibility. Recently, we reported that in patients with BD, CYP2C9 seems to be down-regulated due to inflammation. In the same Turkish patients with BD, we investigated whether also CYP2C19 activity is decreased. Lansoprazole (30 mg) was given as a probe drug to evaluate CYP2C19 activity in 59 patients with BD and 27 healthy control volunteers. An HPLC method was used to determine plasma lansoprazole and its metabolite, 5-hydroxy lansoprazole, concentrations. The genotyping for CYP2C19 *2, *3 and *17 polymorphisms was made using PCR-RFLP. The median lansoprazole/5-hydroxy lansoprazole metabolic ratio (MR) in patients with BD was 2.6-fold higher as compared to the healthy control group (p = 0.001, 22.6 (1.3-26) and 8.8 (0.5-140) as median and range, respectively). The CYP2C19*17*17 genotype frequency was found to be significantly less in the BD group as compared to the healthy controls (1.7% versus 14.8% in controls, p = 0.01). Additionally, colchicine treatment did not affect the CYP2C19 enzyme activity in six patients (p = 0.43). In conclusion, the patients with BD had lower CYP2C19 enzyme activity and lower frequency of the CYP2C19*17 allele as compared to those of the healthy controls. Further studies are warranted on the mechanisms underlying this relation. This study should also be applied to other autoimmune diseases similarly characterized by local or systemic inflammation.

ABSTRACT The objectives of this study were to characterize the population pharmacokinetics (PK) of efavirenz (EFV) and 8-hydroxy-efavirenz (8OHEFV) in plasma and peripheral blood mononuclear cells (PBMCs) and to explore covariates affecting the PK parameters. Fifty-one patients had steady-state 0-to-24-h concentrations of EFV and 8OHEFV in plasma with corresponding concentrations in PBMCs, while 261 patients had one or two sparse concentrations at 16 ± 1 h postdose at weeks 4 and/or 16. The pharmacogenetic markers CYP2B6*6, CYP3A5*3, CYP3A5*6, UGT2B7*2, ABCB1 (3435C→T, 3842A→G), OATP1B1*1B, and OATP1B1*5, the presence of a rifampin-based antituberculosis (anti-TB) regimen, baseline body weight and organ function values, and demographic factors were explored as covariates. EFV concentration data were well described by a two-compartment model with first-order absorption (Ka) and absorption lag time (Alag) (Ka = 0.2 h−1; Alag = 0.83 h; central compartment clearance [CLc/F] for CYP2B6*1/*1 = 18 liters/h, for CYP2B6*1/*6 = 14 liters/h, and for CYP2B6*6/*6 = 8.6 liters/h) and PBMCs as a peripheral compartment. EFV transfer from plasma to PBMCs was first order (CLp/F = 32 liters/h), followed by capacity-limited return (Vmax = 4,400 ng/ml/h; Km = 710 ng/ml). Similarly, 8OHEFV displayed a first-order elimination and distribution to PBMCs, with a capacity-limited return to plasma. No covariate relationships resulted in a significant explanation of interindividual variability (IIV) on the estimated PK parameters of EFV and 8OHEFV, except for CYP2B6*6 genotypes, which were consistent with prior evidence. Both EFV and 8OHEFV accumulated to higher concentrations in PBMCs than in plasma and were well described by first-order input and Michaelis-Menten kinetics removal from PBMCs. CYP2B6*6 genotype polymorphisms were associated with decreased EFV and 8OHEFV clearance.

We compared the pharmacokinetic (PK) exposure parameters of efavirenz (EFV) and its major inactive metabolite, 8-hydroxy-efavirenz (8-OH-EFV), in an open-label, single-sequence, and parallel design of HIV-infected and tuberculosis (TB)-HIV-coinfected Ethiopian patients in the HIV-TB Pharmagene study with 20 and 33 patients, respectively. Both treatment groups underwent PK sampling following oral 600 mg EFV in week 16 of initiating EFV-based combination antiretroviral therapy. The TB-HIV-coinfected group repeated the PK sampling 8 weeks after stopping rifampin (RIF)-based anti-TB treatment. Between-treatment group analysis indicated no significant effect of RIF-based anti-TB cotreatment on PK exposure parameters of EFV, nor was there a significant effect after controlling for sex or CYP2B6 genotype. However, RIF-based therapy in TB-HIV-coinfected patients had significantly increased 8-OH-EFV PK exposure measures and metabolic ratio relative to HIV-only patients, AUC0-24 greater by 79%. The effect was more prominent in women and CYP2B6*6 carriers in within-sex and CYP2B6 genotype comparisons. Within-subject comparisons for AUC0-24 and Cmax when "on" and "off" RIF-based anti-TB cotreatment showed geometric mean ratios (90% confidence intervals) of 100.5% (98.7%-102.3%) and 100.2% (98.1%-102.4%), respectively, for EFV and 98.6% (95.5%-101.7%-) and 97.6% (92.2%-103.0%), respectively, for 8-OH-EFV. We report no significant influence of RIF-based anti-TB cotherapy on the EFV PK exposure measures. The study also calls for caution related to higher exposure to 8-OH-EFV during simultaneous coadministration of EFV and RIF-based anti-TB regimens, which may be associated with neurotoxicity, particularly in female patients and CYP2B6*6 carriers.

BackgroundInitiation of efavirenz-based combination antiretroviral therapy (cART) is associated with Vitamin D deficiency, but the risk factors for cART-induced severe vitamin D deficiency (SVDD) and the impact of anti-tuberculosis (TB) co-treatment is not explored well.MethodsTreatment-naïve HIV patients with (n=102) or without (n=89) tuberculosis co-infection were enrolled prospectively and received efavirenz-based cART. In TB-HIV co-infected patients, rifampicin-based TB treatment was initiated. Plasma 25-hydroxyvitamin D (25(OH)D), cholesterol and 4-beta hydroxycholesterol concentrations were measured at baseline, and weeks 4, 16 and 48 of cART. Plasma efavirenz concentrations were determined at week 4 and 16 of cART. Genotyping for CYP2B6, CYP3A5, ABCB1, SLCO1B1, and UGT2B7 were done.ResultsTB-HIV patients had significantly lower plasma 25(OH)D3 levels than HIV-only patients at baseline. TB co-infection, low Karnofsky score, high viral load and high CYP3A activity as measured by plasma 4-beta hydroxycholesterol/ cholesterol ratios were significant predictors of low 25(OH) D3 levels at baseline. In HIV-only patients, initiation of efavirenz-based cART increased the prevalence of SVVD from 27% at baseline to 76%, 79% and 43% at weeks 4, 16 and 48 of cART, respectively. The median 25(OH)D3 levels declined from baseline by –40%, –50% and –14% at weeks 4, 16 and 48 of cART, respectively. In TB-HIV patients, prior TB therapy had no influence on 25(OH)D3 levels, but the initiation of efavirenz-based cART increased the prevalence of SVDD from 57% at baseline to 70% and 72% at weeks 4 and 16 of cART, respectively. Whereas the median plasma 25(OH)D3 declined from baseline by –17% and –21% at week 4 and 16 of cART, respectively. None of the genotypes were significantly associated with SVDD.ConclusionsLow plasma cholesterol, high CYP3A activity, and high plasma efavirenz concentrations are significant predictors of early efavirenz-based cART-induced SVDD. Low plasma 25(OH)D3 level at baseline is associated with TB co-infection and HIV diseases progression.

Aims: The current HIV treatment guidelines are inconsistent about the need for weight-based efavirenz dose adjustment during rifampicin containing antituberculosis (anti-TB) cotreatment. We investigated effect of rifampicin-based anti-TB cotreatment on plasma efavirenz exposure and treatment outcome, considering effect of CYP2B6 genotype and bodyweight. Patients & methods: HIV-only (arm 1, n = 285) or TB–HIV (arm 2, n = 208) coinfected patients were enrolled and received efavirenz-based ART alone or with rifampicin-based anti-TB therapy, respectively. Plasma efavirenz concentrations at 4th and 16th weeks, viral load and CD4 cell count at 24th and 48th weeks were determined. Results: The mean plasma efavirenz concentration at weeks 4 (p = 0.03) and 16 (p = 0.08) was inconsistently higher in arm 2 than arm 1, mainly in CYP2B6*6 carriers. Effect of bodyweight on efavirenz pharmacokinetics was significant only in arm 1, but not in arm 2. Proportion of patients with nondetectable viral load (≤50 copies/ml) at week 24 was higher in arm 1 than arm 2 patients (91.0 vs 76.3%; p = 0.002), but no significant difference was observed at week 48 (89.5 vs 87.8%; p = 0.22). Conclusion: Rifampicin-based anti-TB cotreatment has no significant influence on long-term efavirenz plasma exposure and efficacy. Hence, there is no need to increase the dose of efavirenz during concomitant rifampicin-based anti-TB cotreatment in the sub-Saharan African population.

OBJECTIVE:To assess (1) the variance of plasma clozapine levels; (2) the relative importance of sex, smoking habits, weight, age, and specific genetic variants of cytochrome P450 1A2 (CYP1A2), uridine diphosphate glucuronosyltransferase 1A4 (UGT1A4), and multidrug resistance protein 1 (MDR1) on plasma levels of clozapine; and (3) the relation between plasma clozapine levels, fasting glucose levels, and waist circumference.METHOD:There were 113 patients on clozapine treatment recruited from psychosis outpatient clinics in Stockholm County, Sweden. Patients had genotype testing for single nucleotide polymorphisms: 2 in MDR1, 3 in CYP1A2, and 1 in UGT1A4. Multiple and logistic regression were used to analyze the relations.RESULTS:There was a wide variation in plasma concentrations of clozapine (mean = 1,615 nmol/L, SD = 1,354 nmol/L), with 37% of the samples within therapeutic range (1,100-2,100 nmol/L). Smokers had significantly lower plasma clozapine concentrations than nonsmokers (P ≤ .03). There was a significant association between the rs762551 A allele of CYP1A2 and lower plasma clozapine concentration (P ≤ .05). Increased fasting glucose level was 3.7-fold more frequent in CC and CA genotypes than AA genotype (odds ratio = 0.27; 95% confidence interval, 0.10-0.72). There was no significant relation between higher fasting glucose levels, larger waist circumference, and higher clozapine levels.CONCLUSIONS:It is difficult to predict plasma clozapine concentration, even when known individual and genetic factors are considered. Therefore, therapeutic drug monitoring is recommended in patients who are treated with clozapine.

The use of khat (Catha edulis) while on medication may alter treatment outcome. In particular, the influence of khat on the metabolic activities of drug-metabolizing enzymes is not known. We performed a comparative 1-way crossover study to evaluate the effect of khat on cytochrome P450 (CYP)2D6 and CYP3A4 enzyme activity. After 1 week of khat abstinence, baseline CYP2D6 and CYP3A4 metabolic activities were determined in 40 Ethiopian male volunteers using 30 mg dextromethorphan (DM) as a probe drug and then repeated after 1 week of daily use of 400 g fresh khat leaves. Urinary concentrations of cathinone and cathine were determined to monitor the subjects' compliance to the study protocol. Genotyping for CYP2D6*3 and CYP2D6*4 was done. Plasma DM, dextrorphan and 3-methoxymorphinan concentrations were quantified. CYP2D6 and CYP3A4 enzyme activities were assessed by comparing plasma log DM/dextrorphan and log DM/methoxymorphinan metabolic ratio (MR) respectively in the presence and absence of khat. Cytochrome 2D6 MR was significantly increased from baseline by concurrent khat use (paired t test, P = 0.003; geometric mean ratio, 1.38; 95% confidence interval [95% CI], 1.12-1.53). Moreover, the inhibition of CYP2D6 activity by khat was more pronounced in CYP2D6*1/*1 compared with CYP2D6*1/*4 genotypes (P = 0.01). A marginal inhibition of CYP3A4 activity in the presence of khat was observed (P = 0.24). The mean percentage increase of CYP2D6 and CYP3A4 MR from baseline by khat use was 46% (95% CI, 20-72) and 31% (95% CI, 8-54), respectively. This is the first report linking khat use with significant inhibition of CYP2D6 metabolic activity in humans.