Pharmacokinetics and Safety of Remdesivir in Pregnant and Non-Pregnant Women with COVID-19: Results from IMPAACT 2032.

BACKGROUND: Pregnant people with COVID-19 experience higher risk for severe disease and adverse pregnancy outcomes, but no pharmacokinetic (PK) data exist to support dosing of COVID-19 therapeutics during pregnancy. We report PK and safety data for intravenous remdesivir in pregnancy. METHODS: IMPAACT 2032 was a phase IV prospective, open-label, non-randomized opportunistic study of hospitalized pregnant and non-pregnant women receiving intravenous remdesivir as part of clinical care. Intensive PK sampling was performed on infusion days 3, 4, or 5 with collection of plasma and peripheral blood mononuclear cells (PBMCs). Safety data were recorded from first infusion through 4 weeks post-last infusion and at delivery. Geometric mean ratios (GMR) (90% confidence intervals [CI]) of PK parameters between pregnant and non-pregnant women were calculated. RESULTS: Fifty-three participants initiated remdesivir (25 pregnant; median (IQR) gestational age 27.6 (24.9, 31.0) weeks). Plasma exposures of remdesivir, its two major metabolites (GS-704277 and GS-441524), and the free remdesivir fraction were similar between pregnant and non-pregnant participants. Concentrations of the active triphosphate (GS-443902) in PBMCs increased 2.04-fold (90% CI 1.35, 3.03) with each additional infusion in non-pregnant versus pregnant participants. Three adverse events in non-pregnant participants were related to treatment (one Grade 3; two Grade 2 resulting in treatment discontinuation). There were no treatment-related adverse pregnancy outcomes or congenital anomalies detected. CONCLUSIONS: Plasma remdesivir PK parameters were comparable between pregnant and non-pregnant women, and no safety concerns were identified based on our limited data. These findings suggest no dose adjustments are indicated for intravenous remdesivir during pregnancy.

Safety and Pharmacokinetics of Lopinavir/Ritonavir Oral Solution in Preterm and Term Infants Starting Before 3 Months of Age.

BACKGROUND: Study of liquid lopinavir/ritonavir (LPV/r) in young infants has been limited by concerns for its safety in neonates. METHODS: International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1106 was a phase IV, prospective, trial evaluating the safety and pharmacokinetics of antiretroviral medications administered according to local guidelines to South African preterm and term infants <3 months of age. Safety evaluation through 24-week follow-up included clinical, cardiac and laboratory assessments. Pharmacokinetic data from P1106 were combined with data from International Maternal Pediatric Adolescent AIDS Clinical Trials Network studies P1030 and P1083 in a population pharmacokinetics model used to simulate LPV exposures with a weight-band dosing regimen in infants through age 6 months. RESULTS: Safety and pharmacokinetics results were similar in 13/28 (46%) infants initiating LPV/r <42 weeks postmenstrual age (PMA) and in those starting ≥42 weeks PMA. LPV/r was started at a median (range) age of 47 (13-121) days. No grade 3 or higher adverse events were considered treatment related. Modeling and simulation predicted that for infants with gestational age ≥27 weeks who receive the weight-band dosing regimen, 82.6% will achieve LPV trough concentration above the target trough concentration of 1.0 µg/mL and 56.6% would exceed the observed adult lower limit of LPV exposure of 55.9 µg·h/mL through age 6 months. CONCLUSIONS: LPV/r oral solution was safely initiated in a relatively small sample size of infants ≥34 weeks PMA and >2 weeks of life. No serious drug-related safety signal was observed; however, adrenal function assessments were not performed. Weight-band dosing regimen in infants with gestational age ≥27 weeks is predicted to result in LPV exposures equivalent to those observed in other pediatric studies.

HIV-1 reservoir size after neonatal antiretroviral therapy and the potential to evaluate antiretroviral-therapy-free remission (IMPAACT P1115): a phase 1/2 proof-of-concept study.

BACKGROUND: Infants born with HIV-1 require lifelong antiretroviral therapy (ART). We aimed to assess whether very early ART in neonates might restrict HIV-1 reservoirs, an important step towards ART-free remission. METHODS: IMPAACT P1115 is an ongoing, phase 1/2, proof-of-concept study in which infants were enrolled at 30 research clinics in 11 countries (Brazil, Haiti, Kenya, Malawi, South Africa, Tanzania, Thailand, Uganda, the USA, Zambia, and Zimbabwe) into two cohorts. Infants at least 34 weeks' gestational age at high risk for in-utero HIV-1 with either untreated maternal HIV-1 (cohort 1) or who were receiving pre-emptive triple antiretroviral prophylaxis outside of the study (maternal ART permissible; cohort 2) were included. All infants initiated treatment within 48 h of life. Cohort 1 initiated three-drug nevirapine-based ART, and cohort 2 initiated three-drug nevirapine-based prophylaxis then three-drug nevirapine-based ART following HIV diagnosis by age 10 days. We added twice-daily coformulated oral ritonavir 75 mg/m2 and lopinavir 300 mg/m2 from 14 days of life and 42 weeks postmenstrual age. We discontinued nevirapine 12 weeks after two consecutive plasma HIV-1 RNA levels below limit of detection. We tracked virological suppression, safety outcomes, and meeting a predetermined biomarker profile at age 2 years (undetectable RNA since week 48, HIV-1 antibody-negative, HIV-1 DNA not detected, and normal CD4 count and CD4 percentage) to assess qualification for analytical treatment interruption. This study is registered with ClinicalTrials.gov, NCT02140255. FINDINGS: Between Jan 23, 2015, and Dec 14, 2017, 440 infants were included in cohort 1 and 20 were included in cohort 2. 54 of these infants (34 from cohort 1 and 20 from cohort 2) had confirmed in-utero HIV-1 and were enrolled to receive study ART. 33 (61%) of 54 infants were female and 21 (39%) were male. The estimated probability of maintaining undetectable plasma RNA through to 2 years was 33% (95% CI 17-49) in cohort 1 and 57% (28-78) in cohort 2. Among infants maintaining protocol-defined virological control criteria through to study week 108, seven of 11 (64%, 95% CI 31-89) in cohort 1 and five of seven (71%, 29-96) in cohort 2 had no detected HIV-1 DNA. Ten of 12 (83%, 52-100) in cohort 1 and all seven (100%, 59-100) in cohort 2 tested HIV-1 antibody-negative at week 108. Among 54 infants initiated on very early ART, ten (19%; six in cohort 1 and four in cohort 2) met all criteria for possible analytical treatment interruption. Reversible grade 3 or 4 adverse events occurred in 15 (44%) of 34 infants in cohort 1 and seven (35%) of 20 infants in cohort 2. INTERPRETATION: Very early ART for in-utero HIV-1 can achieve sustained virological suppression in association with biomarkers indicating restricted HIV-1 reservoirs by age 2 years, which might enable potential ART-free remission. FUNDING: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.

Pharmacokinetics and safety of first-line tuberculosis drugs rifampin, isoniazid, ethambutol, and pyrazinamide during pregnancy and postpartum: results from IMPAACT P1026s.

Physiological changes during pregnancy may alter the pharmacokinetics (PK) of antituberculosis drugs. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s was a multicenter, phase IV, observational, prospective PK and safety study of antiretroviral and antituberculosis drugs administered as part of clinical care in pregnant persons living with and without HIV. We assessed the effects of pregnancy on rifampin, isoniazid, ethambutol, and pyrazinamide PK in pregnant and postpartum (PP) persons without HIV treated for drug-susceptible tuberculosis disease. Daily antituberculosis treatment was prescribed following World Health Organization-recommended weight-band dosing guidelines. Steady-state 12-hour PK profiles of rifampin, isoniazid, ethambutol, and pyrazinamide were performed during second trimester (2T), third trimester (3T), and 2-8 of weeks PP. PK parameters were characterized using noncompartmental analysis, and comparisons were made using geometric mean ratios (GMRs) with 90% confidence intervals (CI). Twenty-seven participants were included: 11 African, 9 Asian, 3 Hispanic, and 4 mixed descent. PK data were available for 17, 21, and 14 participants in 2T, 3T, and PP, respectively. Rifampin and pyrazinamide AUC0-24 and C max in pregnancy were comparable to PP with the GMR between 0.80 and 1.25. Compared to PP, isoniazid AUC0-24 was 25% lower and C max was 23% lower in 3T. Ethambutol AUC0-24 was 39% lower in 3T but limited by a low PP sample size. In summary, isoniazid and ethambutol concentrations were lower during pregnancy compared to PP concentrations, while rifampin and pyrazinamide concentrations were similar. However, the median AUC0-24 for rifampin, isoniazid, and pyrazinamide met the therapeutic targets. The clinical impact of lower isoniazid and ethambutol exposure during pregnancy needs to be determined.

Brief Report: Dolutegravir Plasma Protein Binding and Unbound Concentrations During Pregnancy and Postpartum.

BACKGROUND: Clinical interpretation of the reduced dolutegravir (DTG) plasma concentrations reported during pregnancy is complicated by its high plasma protein binding. Plasma proteins significantly decrease during pregnancy, and understanding changes in DTG protein binding and its therapeutically active unbound concentrations are necessary to evaluate the impact of pregnancy changes on DTG pharmacokinetics. METHODS: Retrospective assessment of plasma samples from pregnant women living with HIV enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s study receiving 50 mg DTG film-coated tablets once daily as part of clinical care. Unbound and total DTG concentrations were determined predose (C0) and at maximum (Cmax) concentrations during the second trimester (2T), third trimester (3T), and postpartum (PP). Percentage unbound was calculated as the ratio of ultrafiltrate unbound DTG concentration to total DTG concentration. RESULTS: Twenty-nine mothers were included for protein binding evaluations; 15, 27, and 23 from the 2T, 3T, and PP, respectively. DTG % unbound for C0 and Cmax were significantly different by stage of pregnancy, with 3T significantly higher compared with PP; 1.02% vs. 0.69% (P = 0.0067) for C0 and 0.76% vs. 0.46% for Cmax (P = 0.0056). Median (IQR) unbound concentrations for C0 were 6.3 (4.7-18.4) for the 2T, 8.0 (5.6-16.9) for the 3T, and 13.3 (8.4-22.7) ng/mL PP, significantly different between 2T and PP (P = 0.0039), but not different between 3T and PP (P = 0.46). CONCLUSION: Lower total DTG plasma concentrations during pregnancy coincide with temporal decreases in DTG protein binding, resulting in comparable unbound DTG concentrations during the 3T and PP.

Antiretrovirals for Human Immunodeficiency Virus Treatment and Prevention in Pregnancy.

Safe and effective antiretroviral medications are needed during pregnancy to reduce maternal morbidity and mortality associated with untreated human immunodeficiency virus (HIV) infection and to prevent viral transmission to the infant. Pharmacokinetic studies have helped inform the appropriate dosing of antiretroviral medications during pregnancy. However, data from these studies consistently become available years after initial regulatory approvals in nonpregnant adults. In this article, the authors provide an overview of considerations in use of antiretroviral medications in pregnant people with or at risk for HIV, pharmacokinetic studies that helped support recommended options, and therapies either under active investigation or in need of prospective study.

Physiologically-based pharmacokinetic modeling of remdesivir and its metabolites in pregnant women with COVID-19.

Pregnant individuals are at high risk for severe illness from COVID-19, and there is an urgent need to identify safe and effective therapeutics for this population. Remdesivir (RDV) is a SARS-CoV-2 nucleotide analog RNA polymerase inhibitor. Limited RDV pharmacokinetic (PK) and safety data are available for pregnant women receiving RDV. The aims of this study were to translate a previously published nonpregnant adult physiologically based PK (PBPK) model for RDV to pregnancy and evaluate model performance with emerging clinical PK data in pregnant women with COVID-19. The pregnancy model was built in the Open Systems Pharmacology software suite (Version 10) including PK-Sim® and MoBi® with pregnancy-related changes of relevant enzymes applied. PK were predicted in a virtual population of 1000 pregnant subjects, and prediction results were compared with in vivo PK data from the International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Network  2032 study. The developed PBPK model successfully captured RDV and its metabolites' plasma concentrations during pregnancy. The ratios of prediction versus observation for RDV area under the curve from time 0 to infinity (AUC0-∞ ) and maximum concentration (Cmax ) were 1.61 and 1.17, respectively. For GS-704277, the ratios of predicted versus observed were 0.94 for AUC0-∞ and 1.20 for Cmax . For GS-441524, the ratios of predicted versus observed were 1.03 for AUC0-24 , 1.05 for Cmax , and 1.07 for concentrations at 24 h. All predictions of AUC and Cmax for RDV and its metabolites were within a twofold error range, and about 60% of predictions were within a 10% error range. These findings demonstrate the feasibility of translating PBPK models to pregnant women to potentially guide trial design, clinical decision making, and drug development.

Potential of Long-Acting Products to Transform the Treatment and Prevention of Human Immunodeficiency Virus (HIV) in Infants, Children, and Adolescents.

Long-acting antiretroviral products have the potential to transform human immunodeficiency virus (HIV) prevention and treatment approaches in pediatric populations. Broadly neutralizing antibodies and/or long-acting antiretroviral formulations by injection could dramatically improve provision of HIV prophylaxis and/or early treatment to newborns and infants at risk of HIV infection. Challenges in daily oral antiretroviral administration to toddlers and school age children living with HIV may be relieved by use of long-acting formulations, but the pharmacokinetics and safety of these products in children must be studied before they can enter routine clinical use. Although some initial studies of broadly neutralizing antibodies and injectable long-acting agents in infants and young children are underway, more studies of these and other long-acting products are needed. For many adolescents, compliance with daily medication administration is especially challenging. Long-acting products hold particular promise for adolescents living with HIV as well as those at high risk of HIV acquisition, and adolescents can usually be included in the drug development pipeline simultaneously with adults. Long-acting products have the potential to provide alternatives to lifelong daily oral drug administration across the pediatric age spectrum, leading to more effective prevention and treatment of HIV infection in infants, children, and adolescents.

Effects of Initiating Raltegravir-Based Versus Efavirenz-Based Antiretroviral Regimens During Pregnancy on Weight Changes and Perinatal Outcomes: NICHD P1081.

BACKGROUND: Integrase inhibitors have been associated with excess gestational weight gain that may lead to adverse pregnancy outcomes (APOs). This post hoc analysis of NICHD P1081 compared antepartum changes in weight and body mass index (BMI) in pregnant women initiating raltegravir- or efavirenz-based combined antiretroviral therapy (cART) and examined associations between rates of weight gain and APOs. SETTING: NICHD P1081 enrolled antiretroviral-naive pregnant women living with HIV in the second and third trimester in Brazil, Tanzania, South Africa, Thailand, Argentina, and the United States. METHODS: Two hundred eighty-one women enrolled between 20 and 31 gestational weeks were randomized to raltegravir- or efavirenz-based cART and followed for ≥4 weeks. A low rate of weight gain was defined as <0.18 kg/wk and high as >0.59 kg/wk. We compared weight gain and BMI increase between treatment arms using Kruskal-Wallis tests. Logistic regression was used to investigate the association between weight gain and APOs. RESULTS: Raltegravir-based cART was associated with significantly higher antepartum weight gain (median 0.36 kg/wk versus 0.29 kg/wk, P = 0.01) and BMI increase (median 0.14 kg/m 2 /wk versus 0.11 kg/m 2 /wk, P = 0.01) compared with efavirenz-based treatment. Women on raltegravir had less low weight gain (18% versus 36%) and more high weight gain (21% versus 12%) ( P = 0.001). Women with low weight gain were more likely than those with normal weight gain to have small for gestational age infants or a composite of APOs. CONCLUSIONS: A raltegravir-based antiretroviral regimen was associated with significantly higher antepartum rate of weight gain and BMI increase compared with efavirenz-based treatment in antiretroviral-naive pregnant women.

Assessment of minority frequency pretreatment HIV drug-resistant variants in pregnant women and associations with virologic non-suppression at term.

OBJECTIVE: To assess in ART-naïve pregnant women randomized to efavirenz- versus raltegravir-based ART (IMPAACT P1081) whether pretreatment drug resistance (PDR) with minority frequency variants (<20% of individual's viral quasispecies) affects antiretroviral treatment (ART)-suppression at term. DESIGN: A case-control study design compared PDR minority variants in cases with virologic non-suppression (plasma HIV RNA >200 copies/mL) at delivery to randomly selected ART-suppressed controls. METHODS: HIV pol genotypes were derived from pretreatment plasma specimens by Illumina sequencing. Resistance mutations were assessed using the HIV Stanford Database, and the proportion of cases versus controls with PDR to their ART regimens was compared. RESULTS: PDR was observed in 7 participants (11.3%; 95% CI 4.7, 21.9) and did not differ between 21 cases and 41 controls (4.8% vs 14.6%, p = 0.4061). PDR detected only as minority variants was less common (3.2%; 95% CI 0.2, 11.7) and also did not differ between groups (0% vs. 4.9%; p = 0.5447). Cases' median plasma HIV RNA at delivery was 347c/mL, with most (n = 19/22) showing progressive diminution of viral load but not ≤200c/mL. Among cases with viral rebound (n = 3/22), none had PDR detected. Virologic non-suppression at term was associated with higher plasma HIV RNA at study entry (p<0.0001), a shorter duration of ART prior to delivery (p<0.0001), and randomization to efavirenz- (versus raltegravir-) based ART (p = 0.0085). CONCLUSIONS: We observed a moderate frequency of PDR that did not significantly contribute to virologic non-suppression at term. Rather, higher pretreatment plasma HIV RNA, randomization to efavirenz-based ART, and shorter duration of ART were associated with non-suppression. These findings support early prenatal care engagement of pregnant women and initiation of integrase inhibitor-based ART due to its association with more rapid suppression of plasma RNA levels. Furthermore, because minority variants appeared infrequent in ART-naïve pregnant women and inconsequential to ART-suppression, testing for minority variants may be unwarranted.

Maraviroc Population Pharmacokinetics Within the First 6 Weeks of Life.

BACKGROUND: Treatment and prophylaxis options for neonatal HIV are limited. This study aimed to develop a population pharmacokinetic model to characterize the disposition of maraviroc in neonates to inform dosing regimens and expand available options. METHODS: Using maraviroc concentrations from neonates who received either a single dose or multiple doses of 8 mg/kg of maraviroc in the first 6 weeks of life, a population pharmacokinetic model was developed to determine the effects of age, sex, maternal efavirenz exposure and concomitant ARV therapy on maraviroc disposition. The final model was used in Monte Carlo simulations to generate expected exposures with recommended dosing regimens. RESULTS: A total of 396 maraviroc concentrations, collected in the first 4 days of life, at 1 week, at 4 weeks and at 6 weeks, from 44 neonates were included in the analysis. After allometrically scaling for weight, age less than 4 days was associated with a 44% decreased apparent clearance compared with participants 7 days to 6 weeks of life. There were no differences identified in apparent clearance or volume of distribution from ages 7 days to 6 weeks, sex, maternal efavirenz exposure or concomitant nevirapine therapy. Monte Carlo simulations with FDA-approved weight band dosing resulted in the majority of simulated patients (84.3%) achieving an average concentration of ≥75 ng/mL. CONCLUSIONS: While maraviroc apparent clearance is decreased in the first few days of life, the current FDA-approved maraviroc weight band dosing provides maraviroc exposures for neonates in the first 6 weeks of life, which were consistent with adult maraviroc exposure range. Maraviroc provides another antiretroviral treatment option for very young infants.

Influence of NAT2 Genotype and Maturation on Isoniazid Exposure in Low-Birth-Weight and Preterm Infants With or Without Human Immunodeficiency Virus (HIV) Exposure.

BACKGROUND: Isoniazid (INH) metabolism depends on the N-acetyl transferase 2 (NAT2) enzyme, whose maturation process remains unknown in low birth weight (LBW) and preterm infants. We aimed to assess INH exposure and safety in infants receiving oral tuberculosis prevention. METHODS: This population pharmacokinetics (PK) analysis used INH and N-acetyl-isoniazid (ACL) concentrations in infants (BW ≤ 4 kg), including preterm, with follow-up for 6 months. PK parameters were described using nonlinear mixed effects modeling. Simulations were performed to assess INH exposure and optimal dosing regimens, using 2 targets: Cmax at 3-6 mg/L and area under the curve (AUC) ≥ 10.52 mg h/L. RESULTS: We included 57 infants (79% preterm, 84% LBW) in the PK analysis, with a median (range) gestational age of 34 (28.7-39.4) weeks. At the time of sampling, postnatal age was 2.3 (0.2-7.3) months and weight (WT) was 3.7 (0.9-9.3) kg. NAT2 genotype was available in 43 (75.4%) patients (10 slow, 26 intermediate, and 7 fast metabolizers). Ninety percent of NAT2 maturation was attained by 4.4 post-natal months. WT, postmenstrual age, and NAT2 genotype significantly influenced INH exposure, with a 5-fold difference in AUC between slow and fast metabolizers for the same dose. INH appeared safe across the broad range of exposure for 61 infants included in the safety analysis. CONCLUSIONS: In LBW/preterm infants, INH dosing needs frequent adjustment to account for growth and maturation. Pharmacogenetics-based dosing regimens is the most powerful approach to deliver safe and equalized exposures for all infants, because NAT2 genotype highly impacts INH pharmacokinetic variability.

Pharmacokinetics of Tenofovir Alafenamide With Boosted Protease Inhibitors in Pregnant and Postpartum Women Living With HIV: Results From IMPAACT P1026s.

BACKGROUND: Tenofovir alafenamide (TAF) is a key component of HIV treatment, but pharmacokinetic data supporting the use of TAF during pregnancy are limited. In this study, we report pharmacokinetic, safety, and birth outcomes for TAF 25 mg with a boosted protease inhibitor in pregnant women living with HIV. METHODS: IMPAACT P1026s was a multicenter, nonrandomized, open-label, phase IV prospective study. Pregnant women living with HIV receiving TAF 25 mg with a boosted protease inhibitor were eligible. Intensive pharmacokinetic assessments were performed during the second and third trimesters and 6-12 weeks postpartum. Maternal and cord blood samples were collected at delivery. Infant washout samples were collected through 5-9 days postbirth. Comparisons of paired pharmacokinetic data between pregnancy and postpartum were made using geometric mean ratios (GMR) [90% confidence intervals (CIs)] and Wilcoxon signed-rank tests with P < 0.10 considered significant. RESULTS: Twenty-nine women were enrolled from the United States (median age 31 years and weight 84.5 kg during the third trimester; 48% Black, 45% Hispanic/Latina). TAF AUCtau did not significantly differ in the second [GMR 0.62 (90% CI: 0.29 to 1.34); P = 0.46] or third trimester [GMR 0.94 (90% CI: 0.63 to 1.39); P = 0.50] vs. postpartum and were comparable with historical data in nonpregnant adults. TAF was only quantifiable in 2/25 maternal delivery samples and below the limit of quantification in all cord blood and infant washout samples, likely because of the short half-life of TAF. CONCLUSION: TAF AUCtau did not significantly differ between pregnancy and postpartum. These findings provide reassurance as TAF use during pregnancy continues to expand.

Interactions between etonogestrel-releasing contraceptive implant and 3 antiretroviral regimens.

OBJECTIVES: Long-acting reversible contraceptives are effective contraceptives for women with HIV, but there are limited data on etonogestrel implant and antiretroviral therapy pharmacokinetic drug-drug interactions. We evaluated etonogestrel/antiretroviral therapy drug-drug interactions, and the effects of etonogestrel on ritonavir-boosted-atazanavir, ritonavir-boosted-lopinavir, and efavirenz pharmacokinetics. STUDY DESIGN: We enrolled postpartum women using etonogestrel implants and receiving ritonavir-boosted-atazanavir, ritonavir-boosted-lopinavir, or efavirenz-based regimens between 2012 and 2015. Etonogestrel implants were inserted 2 to 12 weeks postpartum. We performed pharmacokinetic sampling pre-etonogestrel insertion and 6 to 7 weeks postinsertion. We measured antiretroviral concentrations pre and postetonogestrel insertion, and compared etonogestrel concentrations between antiretroviral regimens. We considered a minimum serum etonogestrel concentration of 90 pg/mL adequate for ovulation suppression. RESULTS: We collected pharmacokinetic data for 74 postpartum women, 22 on ritonavir-boosted-atazanavir, 26 on ritonavir-boosted-lopinavir, and 26 on efavirenz. The median serum concentrations of etonogestrel when co-administered were highest with etonogestrel/ritonavir-boosted-atazanavir (604 pg/mL) and etonogestrel/ritonavir-boosted-lopinavir (428 pg/mL), and lowest with etonogestrel/efavirenz (125 pg/mL); p < 0.001. Minimum concentration (Cmin) of ritonavir-boosted-atazanavir and ritonavir-boosted-lopinavir were lower after etonogestrel implant insertion, but overall exposure, predose concentrations, clearance, and half-lives were unchanged. We found no significant change in efavirenz exposure after etonogestrel insertion. CONCLUSIONS: Unlike efavirenz, ritonavir-boosted-atazanavir and ritonavir-boosted-lopinavir were not associated with significant decreases in etonogestrel concentrations. Efavirenz was associated with a significant decrease in etonogestrel concentrations. IMPLICATIONS: The findings demonstrate no interactions between etonogestrel and ritonavir-boosted-lopinavir or ritonavir-boosted-atazanavir, but confirm the decreased efficacy of etonogestrel with efavirenz-based antiretrovirals. This information should be used to counsel women with HIV who desire long-acting reversible contraceptives.

Optimizing Dolutegravir Initiation in Neonates Using Population Pharmacokinetic Modeling and Simulation.

BACKGROUND: A knowledge gap exists for dolutegravir (DTG) pharmacokinetics and safety during the first 4 weeks of life, preventing safe and effective DTG use in neonates. SETTING: Population pharmacokinetic modeling and simulation were used to assess newborn DTG dosing requirements during the first few days of life as a function of maternal DTG dosing history before delivery. METHODS: DTG PK data were obtained from pregnant women and infants enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026S study. Maternal and neonate population pharmacokinetic models were separately developed. Monte Carlo simulations were performed to simulate neonatal concentrations after 2 doses of DTG after birth for infants born to mothers either receiving or not receiving DTG before delivery. RESULTS: In DTG-naïve infants, a 5-mg DTG dose at birth with a second dose after 48 hours maintained median concentrations above the lower bound of the target range (0.77 µg/mL) and below the upper bound of the target range (7.34 µg/mL representing 2-fold above the adult Cmax value). In DTG-exposed infants, a 5-mg DTG dose at 24 hours after birth with a second dose after 48 hours maintained median concentrations within or nearly within the target range, even if the last maternal DTG dose was taken as soon as 6 hours or as long as 24 hours before delivery. CONCLUSIONS: Newborn DTG dosing requirements during the first few days of life depend on maternal DTG dosing history before delivery. These results may help the design of future clinical studies of DTG in the neonatal population.

Pharmacokinetics of Atazanavir Boosted With Cobicistat in Pregnant and Postpartum Women With HIV.

BACKGROUND: This study evaluated atazanavir and cobicistat pharmacokinetics during pregnancy compared with postpartum and in infant washout samples. SETTING: A nonrandomized, open-label, parallel-group, multicenter prospective study of atazanavir and cobicistat pharmacokinetics in pregnant women with HIV and their children. METHODS: Intensive steady-state 24-hour pharmacokinetic profiles were performed after administration of 300 mg of atazanavir and 150 mg of cobicistat orally in fixed-dose combination once daily during the second trimester, third trimester, and postpartum. Infant washout samples were collected after birth. Atazanavir and cobicistat were measured in plasma by validated high-performance liquid chromatography-ultraviolet and liquid chromatography-tandem mass spectrometry assays, respectively. A 2-tailed Wilcoxon signed-rank test (α = 0.10) was used for paired within-participant comparisons. RESULTS: A total of 11 pregnant women enrolled in the study. Compared with paired postpartum data, atazanavir AUC0-24 was 26% lower in the second trimester [n = 5, P = 0.1875, geometric mean of ratio (GMR) = 0.739, 90% CI: 0.527 to 1.035] and 54% lower in the third trimester (n = 6, GMR = 0.459, P = 0.1563, 90% CI: 0.190 to 1.109), whereas cobicistat AUC0-24 was 35% lower in the second trimester (n = 5, P = 0.0625, GMR = 0.650, 90% CI: 0.493 to 0.858) and 52% lower in the third trimester (n = 7, P = 0.0156, GMR = 0.480, 90% CI: 0.299 to 0.772). The median (interquartile range) 24-hour atazanavir trough concentration was 0.21 µg/mL (0.16-0.28) in the second trimester, 0.21 µg/mL (0.11-0.56) in the third trimester, and 0.61 µg/mL (0.42-1.03) in postpartum. Placental transfer of atazanavir and cobicistat was limited. CONCLUSIONS: Standard atazanavir/cobicistat dosing during pregnancy results in lower exposure which may increase the risk of virologic failure and perinatal transmission.

Abacavir dosing in neonates from birth to 3 months of life: a population pharmacokinetic modelling and simulation study.

BACKGROUND: No evidence-based optimal dosing guidance is available for abacavir liquid formulation use from birth. We used abacavir pharmacokinetic data from neonates and infants to determine an exact abacavir dosing strategy (mg/kg) for infants aged 0-3 months and to propose dosing by WHO weight band for neonates. METHODS: Abacavir pharmacokinetic and safety data were pooled from three completed studies (1997-2020): PACTG 321 (USA), the Tygerberg Cohort (South Africa), and IMPAACT P1106 (South Africa). PACTG 321 and the Tygerberg Cohort were performed in neonates exposed to HIV receiving a single dose of abacavir. IMPAACT P1106 included predominantly low birthweight (<2500 g) infants on antiretroviral therapy enrolled when they were younger than 3 months. We developed a population pharmacokinetic model and performed simulations to achieve abacavir exposures (area under the curve for 0-12 h) within the target range of 3·2-25·2 µg·h/mL, previously reported in older children. FINDINGS: 45 infants contributed 308 abacavir concentrations; 21 neonates were younger than 15 days. At first pharmacokinetic assessment, median postnatal age for PACTG 321 was 1 day and median bodyweight was 3·1 kg; for the Tygerberg Cohort it was 10 days and 3·3 kg; and for IMPAACT P1106 it was 73 days and 3·8 kg. Our model predicted a slow abacavir clearance of 2·51 mL/min per kg at birth, which doubled by 4 weeks of age. Therapeutic targets were achieved with exact abacavir doses of 2·0 mg/kg twice daily from 0 weeks to 4 weeks and 4·0 mg/kg twice daily from 4 weeks to 12 weeks. A fixed weight-band dosing strategy of 8 mg (for 2-3 kg), 10 mg (3-4 kg), and 12 mg (4-5 kg) abacavir twice daily achieved target exposures throughout the first 4 weeks of life without the need for dose adjustment due to age or bodyweight changes. No adverse events of grade 3 or higher were related to abacavir. INTERPRETATION: Integration of these dosing strategies into national and international guidelines for the abacavir liquid formulation will expand antiretroviral options from birth and simplify the clinical management of neonates with HIV. FUNDING: National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Mental Health, and the Collaborative Initiative for Paediatric HIV Education and Research Programme.

Characterization of Plasma Protein Alterations in Pregnant and Postpartum Individuals Living With HIV to Support Physiologically-Based Pharmacokinetic Model Development.

Background: Alterations in plasma protein concentrations in pregnant and postpartum individuals can influence antiretroviral (ARV) pharmacokinetics. Physiologically-based pharmacokinetic (PBPK) models can serve to inform drug dosing decisions in understudied populations. However, development of such models requires quantitative physiological information (e.g., changes in plasma protein concentration) from the population of interest. Objective: To quantitatively describe the time-course of albumin and α1-acid glycoprotein (AAG) concentrations in pregnant and postpartum women living with HIV. Methods: Serum and plasma protein concentrations procured from the International Maternal Pediatric Adolescent AIDS Clinical Trial Protocol 1026s (P1026s) were analyzed using a generalized additive modeling approach. Separate non-parametric smoothing splines were fit to albumin and AAG concentrations as functions of gestational age or postpartum duration. Results: The analysis included 871 and 757 serum albumin concentrations collected from 380 pregnant (~20 to 42 wks gestation) and 354 postpartum (0 to 46 wks postpartum) women, respectively. Thirty-six and 32 plasma AAG concentrations from 31 pregnant (~24 to 38 wks gestation) and 30 postpartum women (~2-13 wks postpartum), respectively, were available for analysis. Estimated mean albumin concentrations remained stable from 20 wks gestation to term (33.4 to 34.3 g/L); whereas, concentrations rapidly increased postpartum until stabilizing at ~42.3 g/L 15 wk after delivery. Estimated AAG concentrations slightly decreased from 24 wks gestation to term (53.6 and 44.9 mg/dL) while postpartum levels were elevated at two wks after delivery (126.1 mg/dL) and subsequently declined thereafter. Computational functions were developed to quantitatively communicate study results in a form that can be readily utilized for PBPK model development. Conclusion: By characterizing the trajectory of plasma protein concentrations in pregnant and postpartum women living with HIV, our analysis can increase confidence in PBPK model predictions for HIV antiretrovirals and better inform drug dosing decisions in this understudied population.