Drug-Drug Interactions with Antiretroviral Drugs in Pregnant Women Living with HIV : Are They Different from Non-Pregnant Individuals?

Although the separate effects of drug-drug interactions and pregnancy on antiretroviral drug pharmacokinetics have been widely studied and described, their combined effect is largely unknown. Physiological changes during pregnancy may change the extent or clinical relevance of a drug-drug interaction in a pregnant woman. This review aims to provide a detailed overview of the mechanisms, magnitude, and clinical significance of antiretroviral drug-drug interactions in pregnant women. We performed a literature search and selected studies that compared the magnitude of drug-drug interactions with antiretroviral drugs in pregnant vs non-pregnant women. Forty-eight papers examining drug-drug interactions during pregnancy were selected, of which the majority focused on pharmacokinetic boosting. Other selected studies examined the drug-drug interactions between efavirenz and lumefantrine, efavirenz and tuberculosis drugs, etravirine and tenofovir disoproxil fumarate, atazanavir and tenofovir disoproxil, and mefloquine and nevirapine in pregnant compared to non-pregnant women. The clinical significance of antiretroviral drug-drug interactions changed during pregnancy from a minimal effect to a contra-indication. In almost all cases, the clinical significance of a drug-drug interaction was more relevant in pregnant women, owing to the combined effects of pregnancy-induced physiological changes and drug-drug interactions leading to a lower absolute drug exposure. Multiple studies show that the clinical relevance of a drug-drug interaction can change during pregnancy. Unfortunately, many potential interactions have not been studied in pregnancy, which may place pregnant women living with human immunodeficiency virus and their newborns at risk

Pharmacokinetic Data of Dolutegravir in Second-line Treatment of Children With Human Immunodeficiency Virus: Results From the CHAPAS4 Trial

BACKGROUND: Dolutegravir (DTG), combined with a backbone of two NRTIs, is currently the preferred first-line treatment for HIV in childhood. CHAPAS4 is an ongoing randomized controlled trial (#ISRCTN22964075) investigating second-line treatment options for children with HIV. We did a nested PK substudy within CHAPAS4 to evaluate the DTG exposure in children with HIV taking DTG with food, as part of their second-line treatment. METHODS: Additional consent was required for children on DTG enrolled in the CHAPAS4-trial to participate in this PK substudy. Children weighing 14-19.9 kg took 25 mg DTG as dispersible tablets (DT) and children ≥20 kg took 50 mg film-coated tablets (FCT). Steady-state 24 h DTG plasma concentration-time PK profiling was done at t = 0 and 1, 2, 4, 6, 8, 12, and 24 h after observed DTG intake with food. Reference adult PK data and paediatric data from the ODYSSEY-trial was used primarily for comparison. The individual target trough concentration (Ctrough) was defined as 0.32 mg/L. RESULTS: 39 children on DTG were included in this PK substudy. The Geometric Mean (GM), (CV%) AUC0-24h was 57.1 h*mg/L (38.4%) which was approximately 8% below the average AUC0-24h in children in the ODYSSEY-trial with comparable dosages, but above the adult reference. The GM (CV%) Ctrough was 0.82 mg/L (63.8%) which was comparable to ODYSSEY and adult reference values. CONCLUSIONS: This nested PK substudy shows that the exposure of DTG taken with food in children on second-line treatment is comparable with that of children in the ODYSSEY-trial and adult references

A new paediatric formulation of valaciclovir : development and bioequivalence assessment

Peer reviewedPostprin

Optimizing Pediatric Dosing Recommendations and Treatment Management of Antiretroviral Drugs Using Therapeutic Drug Monitoring Data in Children Living With HIV.

INTRODUCTION: This review summarizes the current dosing recommendations for antiretroviral (ARV) drugs in the international pediatric guidelines of the World Health Organization (WHO), US Department of Health and Human Services (DHHS), and Pediatric European Network for Treatment of AIDS (PENTA), and evaluates the research that informed these approaches. We further explore the role of data generated through therapeutic drug monitoring in optimizing the dosing of ARVs in children. METHODS: A PubMed search was conducted for the literature on ARV dosing published in English. In addition, the registration documentation of European Medicines Agency and the US Food and Drug Administration for currently used ARVs and studies referenced by the WHO, DHHS, and EMA guidelines were screened. Resulting publications were screened for papers containing data on the area under the concentration-time curve, trough concentration, and peak concentration. Studies with enrolled participants with a median or mean age of ?18 years were excluded. No restriction on publishing date was applied. DISCUSSION AND CONCLUSION: Pediatric ARV dosing is frequently based on data obtained from small studies and is often simplified to facilitate dosing in the context of a public health approach. Pharmacokinetic parameters of pediatric ARVs are subject to high interpatient variation and this leads to a potential risk of underdosing or overdosing when drugs are used in real life. To ensure optimal use of ARVs and validate dosing recommendations for children, it is essential to monitor ARV dosing more thoroughly with larger sample sizes and to include diverse subpopulations. Therapeutic drug monitoring data generated in children, where available and affordable, have the potential to enhance our understanding of the appropriateness of simplified pediatric dosing strategies recommended using a public health approach and to uncover suboptimal dosing or other unanticipated issues postmarketing, further facilitating the ultimate goal of optimizing pediatric ARV treatment

Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis

Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1-15), followed by RIF40 (days 16-30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%-115%); tolbutamide, 80% (74%-86%); omeprazole, 55% (47%-65%); dextromethorphan, 77% (68%-86%); midazolam, 62% (49%-78%), and 117% (105%-130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.</p

The Effect of Using Pazopanib With Food vs. Fasted on Pharmacokinetics, Patient Safety, and Preference (DIET Study)

Pazopanib is taken fasted in a fixed oral daily dose of 800 mg. We hypothesized that ingesting pazopanib with food may improve patients' comfort and reduce gastrointestinal (GI) adverse events. Therefore, we investigated the bioequivalent dose of pazopanib when taken with food compared with 800 mg pazopanib taken fasted. In addition, we investigated the differences in GI toxicity, patient satisfaction, and patient's preference for either intake. The intake of 600 mg pazopanib with food resulted in a bioequivalent exposure and was preferred over a standard pazopanib dose without food. No differences were seen in GI toxicities under both intake regimens. Patients seem to be more positive about their feelings about side effects and satisfaction with their therapy when pazopanib was taken with food. Forty-one of the patients (68%) preferred the intake with a continental breakfast

Comparison of dolutegravir- and efavirenz on depression, anxiety and sleep disorders in pregnant and postpartum women living with HIV; a DolPHIN2 substudy.

BackgroundBoth dolutegravir and efavirenz are known to be effective in pregnancy and post-partum to prevent vertical transmission of HIV and to maintain maternal health. Both drugs have also been associated with neuropsychiatric symptoms. To what extent these symptoms occur in pregnant and post-partum women, however, is not yet known.MethodsThis was a secondary analysis of the DolPHIN2 study, a multicenter randomized trial among women presenting late in pregnancy with untreated HIV- who received either a dolutegravir- or efavirenz- containing regimen. Longitudinal measures of depression, anxiety and sleep quality were analyzed during pregnancy and up to 48 weeks post-partum.ResultsAmong 268 women median (IQR) Edinburgh Post Natal depression score (EPDS) scores were 8 (3-11) and highest at enrolment. In the dolutegravir -and efavirenz arm, respectively, 23.7% and 25.6% had an EPDS score above 9, indicating possible or probable depression. Abnormal Hospital Anxiety Depression scores (HADS) (above 11) were seen at least once during follow up in 42 of patients (15.7%), although no differences were seen between treatment arms. No association was found between EPDS, suicidality and HADS scores and the assigned regimen (p = 0.93, 0.97 and 0.18 respectively). Median (IQR) Pittsburgh Sleep Quality index (PSQI) scores for dolutegravir- and efavirenz were 6 (5-7) and 5 (5-6.5) respectively, p = 0.70.ConclusionsNo statistically significant differences were observed between efavirenz- or dolutegravir containing regimens. Rates of depression were high, but decreased over the course of time and confirm the need for psychological support after initial HIV diagnosis in pregnancy

First Pharmacokinetic Data of Tenofovir Alafenamide Fumarate and Tenofovir With Dolutegravir or Boosted Protease Inhibitors in African Children: A Substudy of the CHAPAS-4 Trial

BACKGROUND: We evaluated the pharmacokinetics of tenofovir alafenamide fumarate (TAF) and tenofovir in a subset of African children enrolled in the CHAPAS-4 trial. METHODS: Children aged 3-15 years with human immunodeficiency virus infection failing first-line antiretroviral therapy were randomized to emtricitabine/TAF versus standard-of-care nucleoside reverse transcriptase inhibitor combination, plus dolutegravir, atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. Daily emtricitabine/TAF was dosed according to World Health Organization (WHO)-recommended weight bands: 120/15 mg in children weighing 14 to <25 kg and 200/25 mg in those weighing ≥25 kg. At steady state, 8-9 blood samples were taken to construct pharmacokinetic curves. Geometric mean (GM) area under the concentration-time curve (AUC) and the maximum concentration (Cmax) were calculated for TAF and tenofovir and compared to reference exposures in adults. RESULTS: Pharmacokinetic results from 104 children taking TAF were analyzed. GM (coefficient of variation [CV%]) TAF AUClast when combined with dolutegravir (n = 18), darunavir/ritonavir (n = 34), or lopinavir/ritonavir (n = 20) were 284.5 (79), 232.0 (61), and 210.2 (98) ng*hour/mL, respectively, and were comparable to adult reference values. When combined with atazanavir/ritonavir (n = 32), TAF AUClast increased to 511.4 (68) ng*hour/mL. For each combination, tenofovir GM (CV%) AUCtau and Cmax remained below reference values in adults taking 25 mg TAF with a boosted protease inhibitors. CONCLUSIONS: In children, TAF combined with boosted PIs or dolutegravir and dosed according to WHO-recommended weight bands provides TAF and tenofovir concentrations previously demonstrated to be well tolerated and effective in adults. These data provide the first evidence for use of these combinations in African children. CLINICAL TRIALS REGISTRATION: ISRCTN22964075

Population Pharmacokinetic Modeling of Dolutegravir to Optimize Pediatric Dosing in HIV-1-Infected Infants, Children, and Adolescents

Background and Objective: 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. // Methods: 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. // Results: 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% were male, and 80% were black. The final population pharmacokinetic model was a one-compartment model with first-order absorption and elimination, enabling predictions of dolutegravir concentrations in the pediatric population across weight bands and doses/formulations. The predicted geometric mean trough concentration was comparable to the adult value following a 50-mg daily dose of dolutegravir for all weight bands at recommended doses. Body weight, age, and formulation were significant predictors of dolutegravir pharmacokinetics in pediatrics. Additionally, during an exploratory exposure–safety analysis, no correlation was found between dolutegravir exposure and selected safety endpoints or adverse events. // Conclusions: The dolutegravir dosing in children ≥ 4 weeks of age on an age/weight-band basis provides comparable exposures to those historically observed in adults. Observed pharmacokinetic variability was higher in this pediatric population and no additional safety concerns were observed. These results support the weight-banded dosing of dolutegravir in pediatric participants currently recommended by the World Health Organization

Dolutegravir versus efavirenz when starting HIV therapy in late pregnancy: a randomised controlled trial

Background Late initiation of HIV antiretroviral therapy (ART) in pregnancy is associated with not achieving viral suppression before giving birth and increased mother-to-child transmission of HIV. We aimed to investigate virological suppression before giving birth with dolutegravir compared with efavirenz, when initiated during the third trimester. Methods In this randomised, open-label trial, DolPHIN-2, we recruited pregnant women in South Africa and Uganda aged at least 18 years, with untreated but confirmed HIV infection and an estimated gestation of at least 28 weeks, initiating ART in third trimester. Participants were randomly assigned (1:1) to dolutegravir-based or efavirenz-based therapy. HIV viral load was measured 7 days and 28 days after antiretroviral initiation, at 36 weeks' gestation, and at the post-partum visit (0–14 days post partum). The primary efficacy outcome was a viral load of less than 50 copies per mL at the first post-partum visit, and the primary safety outcome was the occurrence of drug-related adverse events in mothers and infants until the post-partum visit. Longer-term follow-up of mothers and infants continues. This study is registered with ClinicalTrials.gov, NCT03249181. Findings Between Jan 23, and Aug 15, 2018, we randomly assigned 268 mothers to dolutegravir (135) or efavirenz (133). All mothers and their infants were included in the safety analysis, and 250 mothers (125 in the dolutegravir group, 125 in the efavirenz group) and their infants in efficacy analyses, by intention-to-treat analyses. The median duration of maternal therapy at birth was 55 days (IQR 33–77). 89 (74%) of 120 in the dolutegravir group had viral loads less than 50 copies per mL, compared with 50 (43%) of 117 in the efavirenz group (risk ratio 1·64, 95% CI 1·31–2·06). 30 (22%) of 137 mothers in the dolutegravir group reported serious adverse events compared with 14 (11%) of 131 in the efavirenz group (p=0·013), particularly surrounding pregnancy and puerperium. We found no differences in births less than 37 weeks and less than 34 weeks gestation (16·4% vs 3·3%, across both groups). Three stillbirths in the dolutegravir group and one in the efavirenz group were considered unrelated to treatment. Three infant HIV infections were detected, all in the dolutegravir group, and were considered likely to be in-utero transmissions. Interpretation Our data support the revision to WHO guidelines recommending the transition to dolutegravir in first-line ART for all adults, regardless of pregnancy or child-bearing potential. Funding Unitaid