Dolutegravir (DTG) is primarily metabolized by uridine diphosphate glucuronosyltransferases, forming the pharmacologically inactive DTG glucuronide (DTG-gluc). We described the dolutegravir metabolic ratio (DTG-MR; DTG-gluc AUC(0-24h) divided by DTG AUC(0-24h)) in 85 children with HIV aged 3 months to 18 years receiving DTG in the CHAPAS-4 (ISRCTN22964075) and ODYSSEY (NCT02259127) trials. Additionally, we assessed the influence of age, body weight, nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbone, rifampicin use and kidney function on DTG-MR. The overall geometric mean (CV%) DTG-MR was 0.054 (52%). Rifampicin use was the only significant factor associated with DTG-MR (P < .001) in multiple linear regression. DTG-MR geometric mean ratio was 1.81 (95% CI: 1.57-2.08) for children while on vs. off rifampicin. This study showed that overall DTG-MR in children was similar to adults, unaffected by age or NRTI backbone, and increased with rifampicin co-administration. These findings support future paediatric pharmacokinetic modelling and extrapolation from adult data.

HIV treatment options remain limited in children. Dolutegravir is a potent and well-tolerated, once-daily HIV-1 integrase inhibitor recommended for HIV-1 infection in both adults and children down to 4 weeks of age. To support pediatric dosing of dolutegravir in children, we used a population pharmacokinetic model with dolutegravir data from the P1093 and ODYSSEY clinical trials. The relationship between dolutegravir exposure and selected safety endpoints was also evaluated. A population pharmacokinetic model was developed with data from P1093 and ODYSSEY to characterize the pharmacokinetics and associated variability and to evaluate the impact of pharmacokinetic covariates. The final population pharmacokinetic model simulated exposures across weight bands, doses, and formulations that were compared with established adult reference data. Exploratory exposure–safety analyses evaluated the relationship between dolutegravir pharmacokinetic parameters and selected clinical laboratory parameters and adverse events. A total of N = 239 participants were included, baseline age ranged from 0.1 to 17.5 years, weight ranged from 3.9 to 91 kg, 50

Background Dolutegravir-based antiretroviral therapy is a preferred first-line treatment for adults and children living with HIV; however, very little pharmacokinetic data for dolutegravir use are available in young children. We therefore aimed to evaluate dolutegravir dosing and safety in children weighing 3 kg to less than 20 kg by assessing pharmacokinetic parameters and safety data in children taking dolutegravir within the ODYSSEY trial. Methods We did pharmacokinetic substudies nested within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial. We enrolled children from seven research centres in South Africa, Uganda, and Zimbabwe. Children weighing 3 kg to less than 14 kg received 5 mg dispersible tablets of dolutegravir according to WHO weight bands: 5 mg for children weighing 3 kg to less than 6 kg and younger than 6 months, 10 mg for children weighing 3 kg to less than 6 kg and aged 6 months or older, 15 mg for children weighing 6 kg to less than 10 kg, and 20 mg for children weighing 10 kg to less than 14 kg. Children weighing 14 kg to less than 20 kg received a 25 mg film-coated tablet once per day early in the trial or 25 mg dispersible tablets (five 5 mg tablets once per day) later in the trial. A minimum of eight children per weight band or dose was targeted for 24 h pharmacokinetic profiling at steady state. The primary pharmacokinetic parameter was the trough concentration 24 h after observed dolutegravir intake (C-trough). Pharmacokinetic targets were based on adult dolutegravir C-trough and the 90% effective concentration (EC90; ie, 0.32 mg/L). Safety was evaluated in eligible children consenting to pharmacokinetic substudies. Findings Between May 25, 2017, and Aug 15, 2019, we enrolled 72 children aged between 3 months and 11 years. 71 children were included in the safety population and 55 (76%) of 72 children contributed 65 evaluable pharmacokinetic profiles. Geometric mean C-trough in children on dispersible tablets in weight bands between 3 kg and less than 20 kg ranged between 0.53-0.87 mg/L, comparable to the adult geometric mean C(trough)of 0.83 mg/L. Variability was high with coefficient of variation percentages ranging between 50% and 150% compared with 26% in adults. C-trough below EC90 was observed in four (31%) of 13 children weighing 6 kg to less than 10 kg taking 15 mg dispersible tablets, and four (21%) of 19 weighing 14 kg to less than 20 kg taking 25 mg film-coated tablets. The lowest geometric mean C-trough of 0.44 mg/L was observed in children weighing 14 kg to less than 20 kg on 25 mg film coated tablets. Exposures were 1.7-2.0 times higher on 25 mg dispersible tablets versus 25 mg film-coated tablets. 19 (27%) of 71 children had 29 reportable grade 3 or higher adverse events (13 serious adverse events, including two deaths), none of which were related to dolutegravir. Interpretation Weight-band dosing of paediatric dolutegravir dispersible tablets provides appropriate drug exposure in most children weighing 3 kg to less than 20 kg, with no safety signal. 25 mg film-coated tablets did not achieve pharmacokinetic parameters in children weighing 14 kg to less than 20 kg, which were comparable to adults, suggesting dosing with dispersible tablets is preferable or a higher film-coated tablet dose is required. Funding Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, and UK Medical Research Council. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

BACKGROUND:Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. METHODS:We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0-24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014-002632-14), and the ISRCTN registry (ISRCTN91737921). FINDINGS:Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4-17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08-2·11) for Ctrough, 1·23 (0·99-1·53) for AUC0-24 h, and 0·94 (0·76-1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30-40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. INTERPRETATION:Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB. FUNDING:Penta Foundation, ViiV Healthcare, UK Medical Research Council.

BACKGROUND:Pharmacokinetic and efficacy data on dolutegravir in pregnant women living with human immunodeficiency virus (HIV) are still limited but needed to support its use as one of the preferred antiretroviral agents.METHODS:Within the multicenter Pharmacokinetics of ANtiretroviral agents in HIV-infected pregNAnt women (PANNA) study, pregnant women living with HIV and using dolutegravir once daily (50 mg, with food) underwent 24-hour pharmacokinetic profiling in their third trimester and postpartum. Dolutegravir exposure in the third trimester was considered adequate if geometric mean unbound, pharmacologically active, minimal plasma concentrations (Cmin, unbound) and ≥90% of individual Cmin, unbound levels were >0.85 µg/L, the proposed 90% inhibitory concentration for unbound dolutegravir. Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) for comparison of total and unbound pharmacokinetic parameters in the third trimester and postpartum were calculated, including the metabolic ratio for dolutegravir-glucuronide. Safety and virological data were collected.RESULTS:Seventeen women (76% black) were enrolled (25 evaluable pharmacokinetic profiles; 15 in the third trimester, 10 in postpartum). In the third trimester, geometric mean (coefficient of variation, %) Cmin, unbound was 2.87 (87) µg/L and 93% of individual Cmin, unbound levels were >0.85 µg/L. The GMR (90% CI) in the third trimester vs postpartum was 0.86 (.68-1.10) for area under the curve (AUC0-24h), and for Cmax, 0.93 (.77-1.13). GMR (90% CI) for the trough concentrations was 0.71 (.49-1.02), based on total dolutegravir concentrations. Four serious adverse events were reported, unlikely related to dolutegravir. The HIV polymerase chain reaction test was negative in 14/17 infants (result unknown for 3 infants).CONCLUSIONS:Pharmacokinetic changes for dolutegravir in late pregnancy are not clinically relevant and support the use of dolutegravir 50 mg once daily with food in pregnancy.CLINICAL TRIALS REGISTRATION:NCT00825929.

BackgroundPaediatric dolutegravir doses approved by stringent regulatory authorities (SRAs) for children weighing 20 kg to less than 40 kg until recently required 25 mg and 10 mg film-coated tablets. These tablets are not readily available in low-resource settings where the burden of HIV is highest. We did nested pharmacokinetic substudies in patients enrolled in the ODYSSEY-trial to evaluate simplified dosing in children with HIV.MethodsWe did pharmacokinetic and safety substudies within the open-label, multicentre, randomised ODYSSEY trial (NCT02259127) of children with HIV starting treatment in four research centres in Uganda and Zimbabwe. Eligible children were randomised to dolutegravir in ODYSSEY and weighed 20 kg to less than 40 kg. In children weighing 20 kg to less than 25 kg, we assessed dolutegravir's pharmacokinetics in children given once daily 25 mg film-coated tablets (approved by the SRAs at the time of the study) in part one of the study, and 50 mg film-coated tablets (adult dose) or 30 mg dispersible tablets in part two of the study. In children weighing 25 kg to less than 40 kg, we also assessed dolutegravir pharmacokinetics within-subject on film-coated tablet doses of 25 mg or 35 mg once daily, which were approved by the SRAs for the children's weight band; then switched to 50 mg film-coated tablets once daily. Steady-state 24 h dolutegravir plasma concentration-time pharmacokinetic profiling was done in all enrolled children at baseline and 1, 2, 3, 4, 6, and 24 h after observed dolutegravir intake. Target dolutegravir trough concentrations (Ctrough) were based on reference adult pharmacokinetic data and safety was evaluated in all children in the corresponding weight bands who consented to pharmacokinetic studies and received the studied doses.FindingsBetween Sept 22, 2016, and May 31, 2018, we enrolled 62 black-African children aged from 6 years to younger than 18 years (84 pharmacokinetic-profiles). In children weighing 20 kg to less than 25 kg taking 25 mg film-coated tablets, the geometric mean (GM) Ctrough (coefficient of variation) was 0·32 mg/L (94%), which was 61% lower than the GM Ctrough of 0·83 mg/L (26%) in fasted adults on dolutegravir 50 mg once-daily; in children weighing 25 kg to less than 30 kg taking 25 mg film-coated tablets, the GM Ctrough was 0·39 mg/L (48%), which was 54% lower than the GM Ctrough in fasted adults; and in those 30 kg to less than 40 kg taking 35 mg film-coated tablets the GM Ctrough was 0·46 mg/L (63%), which was 45% lower than the GM Ctrough in fasted adults. On 50 mg film-coated tablets or 30 mg dispersible tablets, Ctrough was close to the adult reference (with similar estimates on the two formulations in children in the 20 to <25 kg weight band), with total exposure (area under the concentration-time curve from 0 h to 24 h) in between reference values in adults dosed once and twice daily, where safety data are reassuring, although maximum concentrations were higher in children weighing 20 kg to less than 25 kg than in the twice-daily adult reference. Over a 24-week follow-up period in 47 children on 30 mg dispersible tablets or 50 mg film-coated tablets, none of the three reported adverse events (cryptococcal meningitis, asymptomatic anaemia, and asymptomatic neutropenia) were considered related to dolutegravir.InterpretationAdult dolutegravir 50 mg film-coated tablets given once daily provide appropriate pharmacokinetic profiles in children weighing 20 kg or more, with no safety signal, allowing simplified practical dosing and rapid access to dolutegravir. These results informed the WHO 2019 dolutegravir paediatric dosing guidelines and have led to US Food and Drug Administration approval of adult dosing down to 20 kg.FundingPaediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, UK Medical Research Council.

Background: If HIV patients are unconscious or cannot swallow tablets for other reasons, antiretroviral medication is crushed and dissolved prior to administration. Crushing can alter drug exposure, possibly leading to treatment failure, development of resistance or toxicity. Currently, there is no information about crushing of the branded fixed-dose combination of dolutegravir/abacavir/lamivudine (Triumeq (R) VR, referred to as TRI); therefore, crushing of TRI is not recommended. Objectives: To investigate whether the TRI fixed-dose combination tablet can be crushed and combined with enteral nutrition without influencing pharmacokinetics (PK). Methods: We carried out an open-label, three-period, randomized, single-dose, crossover trial in 22 healthy adult volunteers. Subjects randomly received whole-tablet TRI with fasting (reference), crushed and suspended TRI with fasting or crushed and suspended TRI with oral intake of enteral nutrition. Bioequivalence criteria (80%-125% acceptance range) of AUC(0-infinity) and C-max were used. ClinicalTrials.gov:NCT02569346. Results: Crushing TRI leads to higher dolutegravir exposure (AUC(0-infinity): +26% and C-max: +30%) and, if crushed TRI is combined with enteral nutrition, to a decrease in abacavir C-max (-17%). Lamivudine concentrations were not affected as geometric mean ratios with 90% CIs fell within the 80%-125% range. Conclusions: Bioequivalence could not be demonstrated for a crushed and suspended tablet or a crushed and suspended tablet with oral intake of enteral nutrition compared with whole-tablet TRI with fasting. Both scenarios led to higher dolutegravir exposure, but this did not exceed exposure after intake with food or in twice-daily dosing. In our opinion, TRI can be crushed for patients with swallowing difficulties and can be simultaneously administered with enteral nutrition.

Dolutegravir, elvitegravir, raltegravir, nevirapine and etravirine are antiretroviral drugs used as part of combined antiretroviral treatment for HIV-infection. For quantification of these drugs in human K-2 EDTA plasma samples an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) bioanalytical method was developed and validated. Stable isotope labeled internal standards were used for each analyte. Simple protein precipitation with methanol was implemented to prepare plasma samples of at least 50 mu L. The method was validated for dolutegravir, elvitegravir, raltegravir, nevirapine and etravirine over the ranges 9.7-9700, 52-10,470, 9.7-9730, 73-14,680 and 15-3010 ng/mL, respectively. Within-run and between-run accuracy and precision were within +/- 15% of the nominal concentration for quality controls at high, medium and low concentrations, and within +/- 20% at the lower limit of quantification for all analytes. Recovery was >= 76% and reproducible. Long-term stability of patient plasma samples was demonstrated for at least 12 months at - 40 degrees C (4 months for etravirine). Currently, this robust method with a run time of 10 min is used in clinical research and for therapeutic drug monitoring of these frequently used antiretroviral drugs.

As far as we know, there are no data published on the pharmacokinetics of dolutegravir in HIV-infected patients during any kind of dialysis. The extent of drug dialysability is often hard to predict and depends primarily on physicochemical drug characteristics. Dolutegravir is mainly metabolized by uridine diphosphate glucuronosyl transferase 1A1 in the liver and excreted in the feces. Less than 1% of the unchained dolutegravir is excreted with the urine [1]. Dolutegravir is highly bound to plasma proteins (99%) and its water solubility is low (0.0922 mg/ml). These characteristics make it unlikely for dolutegravir to be dialyzed. In contrast, both the molecular weight of dolutegravir (419 g/mol) and its volume of distribution (Vd = 17.4 l) are relatively low, which should make dolutegravir vulnerable for elimination by hemodialysis [1]. The net effect of these opposite influences of dialysis on dolutegravir pharmacokinetics has not been studied so far. Here, we report on the pharmacokinetics of dolutegravir in a HIV-infected patient undergoing hemodialysis. The medical history of our 63-year-old male patient included thromboangiitis obliterans (Buerger's disease), which led to bilateral lower limb amputation. Malignant hypertension and possibly also tenofovir disoproxil fumarate-related renal toxicity led to chronic renal insufficiency and the need for intermittent hemodialysis three times a week. He was first tested HIV-positive in 2007 (HIV-1 RNA 600 000 copies/ml, CD4+ cell count 140 cells/μl). After efavirenz, tenofovir, and emtricitabine were initiated, his viral load has remained less 50 copies/ml ever since. His regimen was changed to abacavir, efavirenz, and lamivudine at the time when he presented with renal insufficiency. Because the patient received several other concomitant drugs and was at high risk for a new cardiovascular event, his treatment was simplified into dolutegravir monotherapy (50 mg QD). On two consecutive days, blood samples were taken at various time points to obtain a pharmacokinetic curve of dolutegravir plasmaconcentrations with (24 h curve) and without hemodialysis (9.5 h curve). On both days, dolutegravir was administered in the morning, 1.5 h after a standardized breakfast. The 3.5 h during hemodialysis session started 6.5 h after dose. During dialysis, pre and post dialyser samples were taken hourly and also samples from the dialysate were taken. The extraction ratio (ER) for dolutegravir in hemodialysis was calculated with the formula: (Cin–Cout)/Cin. In which Cin represents the plasmaconcentration of dolutegravir in the blood entering the dialyser and Cout the plasmaconcentration of dolutegravir in the blood leaving the dialyser. The dialyser used in this patient was a triacetate hollow fiber dialyser (Sureflux-17UX; Nipro Europe). Directly after obtainment, dolutegravir EDTA blood samples were refrigerated and centrifugated (1900 × g for 5 min) within 2 h. Plasma was stored at −40°C until analysis. Dolutegravir plasmaconcentrations were analyzed by a validated liquid chromatography–mass spectrometry method. At the time of blood sampling, HIV plasma viral load was less than 50 copies/ml. Figure 1 shows the plasmaconcentration vs. time curve for dolutegravir with and without hemodialysis. The plasmaconcentration curves on both days look very similar and there seems to be no clear additional decrease in plasmaconcentration during the hemodialysis session. This is confirmed by the very low mean extraction ratio (ER = 0.0006) that we found for dolutegravir. The Ct=24h concentrations on both days were; 0.195 mg/l (with hemodialysis) and 0.072 mg/l (extrapolated for the day without hemodialysis; showing at least no lower exposure during dialysis). Also, dolutegravir concentrations in the four dialysate samples were undetectable (<0.01 mg/l).Fig. 1: Plasmaconcentration vs. time curve for dolutegravir (DGT) with and without hemodialysis on two consecutive days.Based on these data, we conclude that dolutegravir is not dialyzed during hemodialysis and no dose adjustment is needed in patients receiving intermittent hemodialysis. Noticeable are the low dolutegravir trough concentrations that we found in this patient compared with mean trough concentrations (1.20 mg/l) as found in a population on dolutegravir 50 mg QD [2]. Dolutegravir trough concentrations were approximately 85% lower in our patient and just around 0.10 mg/l, which is seen as the lower limit for virological response of dolutegravir in patients without integrase resistant mutations [3]. Unexpected lower exposures to dolutegravir (AUC0–oo 40% lower) were also seen in HIV-seronegative study participants (n = 8) with severe renal impairment (estimated glomerular filtration rate < 30 ml/min) but without dialysis compared with matched healthy controls [4]. One explanation could be concomitant intake of dolutegravir with cations, which can significantly lower the uptake of dolutegravir [5]. After the sampling days, we heard that our patient was taking calcium carbonate tablets three times a day, as was initiated by the dialysis unit, although we had not witnessed him taking these simultaneously with dolutegravir. In conclusion, our data confirm that dolutegravir is not dialyzed in hemodialysis, but we recommend monitoring dolutegravir trough concentrations in patients with renal impairment or extensive comedication in order to prevent treatment failure. Acknowledgements Data presented previously at the winter meeting of the Dutch Association of HIV-treating physicians at 22 January 2016. Conflicts of interest There are no conflicts of interest.

Introduction: With the introduction of the coformulated dolutegravir, abacavir and lamivudine, a new single tablet regimen (STR) is made available for the use in treatment-naive and treatment-experienced HIV-infected patients. This drug combination is the fourth STR that will be positioned next to the STRs with efavirenz, rilpivirine or elvitegravir as third agents, respectively.Areas covered: The objective of this review is to provide an overview of the efficacy and safety of the combined dolutegravir/abacavir/lamivudine coformulation. The review will focus on dolutegravir and includes both published data as well as data presented at recent major international HIV/AIDS conferences.Expert opinion: The dolutegravir/abacavir/lamivudine regimen is highly effective in achieving sustained suppression of HIV-1 RNA plasma concentrations. The STR has a favorable safety profile and a low potential for drug interactions, which will contribute to a prominent role in therapy. As this STR contains abacavir as backbone component, the use requires patients to be HLA-B*5701 negative, with good hepatic function. Other first-line treatment combinations are preferred for patients with hepatitis B co-infection or with a high cardiovascular risk.