Low-Dose Subcutaneous or Intravenous Monoclonal Antibody to Prevent Malaria.

BACKGROUND: New approaches for the prevention and elimination of malaria, a leading cause of illness and death among infants and young children globally, are needed. METHODS: We conducted a phase 1 clinical trial to assess the safety and pharmacokinetics of L9LS, a next-generation antimalarial monoclonal antibody, and its protective efficacy against controlled human malaria infection in healthy adults who had never had malaria or received a vaccine for malaria. The participants received L9LS either intravenously or subcutaneously at a dose of 1 mg, 5 mg, or 20 mg per kilogram of body weight. Within 2 to 6 weeks after the administration of L9LS, both the participants who received L9LS and the control participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying Plasmodium falciparum (3D7 strain). RESULTS: No safety concerns were identified. L9LS had an estimated half-life of 56 days, and it had dose linearity, with the highest mean (±SD) maximum serum concentration (Cmax) of 914.2±146.5 µg per milliliter observed in participants who had received 20 mg per kilogram intravenously and the lowest mean Cmax of 41.5±4.7 µg per milliliter observed in those who had received 1 mg per kilogram intravenously; the mean Cmax was 164.8±31.1 in the participants who had received 5 mg per kilogram intravenously and 68.9±22.3 in those who had received 5 mg per kilogram subcutaneously. A total of 17 L9LS recipients and 6 control participants underwent controlled human malaria infection. Of the 17 participants who received a single dose of L9LS, 15 (88%) were protected after controlled human malaria infection. Parasitemia did not develop in any of the participants who received 5 or 20 mg per kilogram of intravenous L9LS. Parasitemia developed in 1 of 5 participants who received 1 mg per kilogram intravenously, 1 of 5 participants who received 5 mg per kilogram subcutaneously, and all 6 control participants through 21 days after the controlled human malaria infection. Protection conferred by L9LS was seen at serum concentrations as low as 9.2 µg per milliliter. CONCLUSIONS: In this small trial, L9LS administered intravenously or subcutaneously protected recipients against malaria after controlled infection, without evident safety concerns. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 614 ClinicalTrials.gov number, NCT05019729.).

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.

A Monoclonal Antibody for Malaria Prevention.

BACKGROUND: Additional interventions are needed to reduce the morbidity and mortality caused by malaria. METHODS: We conducted a two-part, phase 1 clinical trial to assess the safety and pharmacokinetics of CIS43LS, an antimalarial monoclonal antibody with an extended half-life, and its efficacy against infection with Plasmodium falciparum. Part A of the trial assessed the safety, initial side-effect profile, and pharmacokinetics of CIS43LS in healthy adults who had never had malaria. Participants received CIS43LS subcutaneously or intravenously at one of three escalating dose levels. A subgroup of participants from Part A continued to Part B, and some received a second CIS43LS infusion. Additional participants were enrolled in Part B and received CIS43LS intravenously. To assess the protective efficacy of CIS43LS, some participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying P. falciparum sporozoites 4 to 36 weeks after administration of CIS43LS. RESULTS: A total of 25 participants received CIS43LS at a dose of 5 mg per kilogram of body weight, 20 mg per kilogram, or 40 mg per kilogram, and 4 of the 25 participants received a second dose (20 mg per kilogram regardless of initial dose). No safety concerns were identified. We observed dose-dependent increases in CIS43LS serum concentrations, with a half-life of 56 days. None of the 9 participants who received CIS43LS, as compared with 5 of 6 control participants who did not receive CIS43LS, had parasitemia according to polymerase-chain-reaction testing through 21 days after controlled human malaria infection. Two participants who received 40 mg per kilogram of CIS43LS and underwent controlled human malaria infection approximately 36 weeks later had no parasitemia, with serum concentrations of CIS43LS of 46 and 57 µg per milliliter at the time of controlled human malaria infection. CONCLUSIONS: Among adults who had never had malaria infection or vaccination, administration of the long-acting monoclonal antibody CIS43LS prevented malaria after controlled infection. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 612 ClinicalTrials.gov number, NCT04206332.).

Interleukin 6 Blockade With Tocilizumab Diminishes Indices of Inflammation That Are Linked to Mortality in Treated Human Immunodeficiency Virus Infection.

BACKGROUND: People with human immunodeficiency virus (PWH) are at increased risk for comorbidities, and plasma interleukin 6 (IL-6) levels are among the most robust predictors of these outcomes. Tocilizumab (TCZ) blocks the receptor for IL-6, inhibiting functions of this cytokine. METHODS: This was a 40-week, placebo-controlled, crossover trial (NCT02049437) where PWH on stable antiretroviral therapy (ART) were randomized to receive 3 monthly doses of TCZ or matching placebo intravenously. Following a 10-week treatment period and a 12-week washout, participants were switched to the opposite treatment. The primary endpoints were safety and posttreatment levels of C-reactive protein (CRP) and CD4+ T-cell cycling. Secondary endpoints included changes in inflammatory indices and lipid levels. RESULTS: There were 9 treatment-related toxicities of grade 2 or greater during TCZ administration (mostly neutropenia) and 2 during placebo administration. Thirty-one of 34 participants completed the study and were included in a modified intent-to-treat analysis. TCZ reduced levels of CRP (median decrease, 1819.9 ng/mL, P < .0001; effect size, 0.87) and reduced inflammatory markers in PWH, including D-dimer, soluble CD14, and tumor necrosis factor receptors. T-cell cycling tended to decrease in all maturation subsets after TCZ administration, but was only significant among naive CD4 T cells. Lipid levels, including lipid classes that have been related to cardiovascular disease risk, increased during TCZ treatment. CONCLUSIONS: TCZ is safe and decreases inflammation in PWH; IL-6 is a key driver of the inflammatory environment that predicts morbidity and mortality in ART-treated PWH. The clinical significance of lipid elevations during TCZ treatment requires further study. Clinical Trials Registration. NCT02049437.

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.

Fexofenadine Plasma Concentrations to Estimate Systemic Exposure in Healthy Adults Using a Limited Sampling Strategy with a Population Pharmacokinetic Approach.

BACKGROUND: Fexofenadine is a recommended in vivo probe drug for phenotyping P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP) 1B1/3 transporter activities. This study evaluated a limited sampling strategy using a population pharmacokinetic approach to estimate plasma fexofenadine exposure as an index of P-gp and OATP activities. METHODS: In a previous study, a single oral dose of fexofenadine (120 mg) was administered alone or in combination with grapefruit juice, Panax ginseng , or Echinacea purpurea to healthy adult participants. Serial plasma samples were collected up to 72 hours after administration and fexofenadine concentrations were measured. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling. Limited sampling models (LSMs) using single and 2-timepoint fexofenadine concentrations were compared with full profiles from intense sampling using empirical Bayesian post hoc estimations of systemic exposure derived from the population pharmacokinetic model. Predefined criteria for LSM selection and validation included a coefficient of determination (R 2 ) ≥ 0.90, relative percent mean prediction error ≥ -5 to ≤5%, relative percent mean absolute error ≤ 10%, and relative percent root mean square error ≤ 15%. RESULTS: Fexofenadine concentrations (n = 1520) were well described using a 2-compartment model. Grapefruit juice decreased the relative oral bioavailability of fexofenadine by 25%, whereas P. ginseng and E. purpurea had no effect. All the evaluated single timepoint fexofenadine LSMs showed unacceptable percent mean prediction error, percent mean absolute error, and/or percent root mean square error. Although adding a second time point improved precision, the predefined criteria were not met. CONCLUSIONS: Identifying novel fexofenadine LSMs to estimate P-gp and OATP1B1/3 activities in healthy adults for future transporter-mediated drug-drug interaction studies remains elusive.

Variable Delta-9-Tetrahydrocannabinol Pharmacokinetics and Pharmacodynamics After Cannabis Smoking in Regular Users.

BACKGROUND: Despite its federally restricted status, cannabis is widely used medicinally and recreationally. The pharmacokinetics (PK) and central nervous system (CNS) effects of tetrahydrocannabinol (THC), the major psychoactive cannabinoid, are not well understood. The objective of this study was to develop a population PK model of inhaled THC, including sources of variability, and to conduct an exploratory analysis of potential exposure-response relationships. METHODS: Regular adult cannabis users smoked a single cannabis cigarette containing 5.9% THC (Chemovar A) or 13.4% THC (Chemovar B) ad libitum. THC concentrations in whole blood were measured and used to develop a population PK model to identify potential factors contributing to interindividual variability in THC PK and to describe THC disposition. Relationships between model-predicted exposure and heart rate, change in composite driving score on a driving simulator, and perceived highness were evaluated. RESULTS: From the 102 participants, a total of 770 blood THC concentrations were obtained. A two-compartment structural model adequately fit the data. Chemovar and baseline THC (THC BL ) were found to be significant covariates for bioavailability, with Chemovar A having better THC absorption. The model predicted that heavy users-those with the highest THC BL -would have significantly higher absorption than those with lighter previous use. There was a statistically significant relationship between exposure and heart rate, and exposure and perceived highness. CONCLUSIONS: THC PK is highly variable and related to baseline THC concentrations and different chemovars. The developed population PK model showed that heavier users had higher THC bioavailability. To better understand the factors affecting THC PK and dose-response relationships, future studies should incorporate a wide range of doses, multiple routes of administration, and different formulations relevant to typical community use.

Safety and Pharmacokinetics of Monoclonal Antibodies VRC07-523LS and PGT121 Administered Subcutaneously for Human Immunodeficiency Virus Prevention.

BACKGROUND: Effective, long-acting prevention approaches are needed to reduce human immunodeficiency virus (HIV) incidence. We evaluated the safety and pharmacokinetics of VRC07-523LS and PGT121 administered subcutaneously alone and in combination as passive immunization for young women in South Africa. METHODS: CAPRISA 012A was a randomized, double-blinded, placebo-controlled, dose-escalation phase 1 trial. We enrolled 45 HIV-negative women into 9 groups and assessed safety, tolerability, pharmacokinetics, neutralization activity, and antidrug antibody levels. Pharmacokinetic modeling was conducted to predict steady-state concentrations for 12- and 24-weekly dosing intervals. RESULTS: VRC07-523LS and PGT121, administered subcutaneously, were safe and well tolerated. Most common reactogenicity events were injection site tenderness and headaches. Nine product-related adverse events were mild and transient. Median VRC07-523LS concentrations after 20 mg/kg doses were 9.65 µg/mL and 3.86 µg/mL at 16 and 24 weeks. The median week 8 concentration after the 10 mg/kg PGT121 dose was 8.26 µg/mL. Modeling of PGT121 at 20 mg/kg showed median concentrations of 1.37 µg/mL and 0.22 µg/mL at 16 and 24 weeks. Half-lives of VRC07-523LS and PGT121 were 29 and 20 days. Both antibodies retained neutralizing activity postadministration and no antidrug antibodies were detected. CONCLUSIONS: Subcutaneous administration of VRC07-523LS in combination with optimized versions of PGT121 or other antibodies should be further assessed for HIV prevention.

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.

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.

Impact of genetic variation in CYP2C19, CYP2D6, and CYP3A4 on oxycodone and its metabolites in a large database of clinical urine drug tests.

Urine drug testing (UDT) is a tool for monitoring drug use, including oxycodone. While variation in cytochrome P450 (CYP) genes is known to alter oxycodone metabolism, its impact on UDT results of oxycodone and its metabolites has not been well-studied. Here, multivariate analysis was performed on retrospective UDT results of 90,379 specimens collected from 14,684 genotyped patients prescribed oxycodone. Genetic variation in CYP2D6 and CYP2C19 had a significant impact on oxymorphone/oxycodone ratios, with a 6.9-fold difference between CYP2D6 ultrarapid metabolizers (UMs) and poor metabolizers (PMs; p < 10-300) and a 1.6-fold difference between CYP2C19 UMs and PMs (p = 1.50 × 10-4). CYP2D6 variation also significantly impacted noroxycodone/oxycodone ratios (p = 6.95 × 10-38). Oxycodone-positive specimens from CYP2D6 PMs were ~5-fold more likely to be oxymorphone-negative compared to normal metabolizers. These findings indicate that multivariate analysis of UDT data may be used to reveal the real-world impact of genetic and non-genetic factors on drug metabolism.

Anakinra Treatment in Patients with Acute Kawasaki Disease with Coronary Artery Aneurysms: A Phase I/IIa Trial.

OBJECTIVES: To determine the safety, pharmacokinetics, and immunomodulatory effects of 2-6 weeks of anakinra therapy in patients with acute Kawasaki disease with a coronary artery aneurysm (CAA). STUDY DESIGN: We performed a Phase I/IIa dose-escalation study of anakinra (2-11 mg/kg/day) in 22 patients with acute Kawasaki disease with CAA. We measured interleukin (IL)-1RA concentrations after the first dose and trough levels up to study week 6. Markers of inflammation and coronary artery z-scores were assessed pretreatment and at 48 hours, 2 weeks, and 6 weeks after initiation of therapy. RESULTS: Up to 6 weeks of anakinra (up to 11 mg/kg/day) was safe and well tolerated by the 22 participants (median age, 1.1 years), with no serious adverse events attributable to the study drug. All participants were treated with intravenous immunoglobulin (IVIG), and 20 also received infliximab (10 mg/kg) before initiation of anakinra. Serum levels of IL-6, IL-8, and tumor necrosis factor α decreased similarly in patients with Kawasaki disease treated with IVIG, infliximab, and anakinra compared with age- and sex-matched patients with Kawasaki disease treated only with IVIG and infliximab. Anakinra clearance increased with illness day at diagnosis. Simulations demonstrated that more frequent intravenous (IV) dosing may result in more sustained concentrations without significantly increasing the peak concentration compared with subcutaneous (SC) dosing. CONCLUSIONS: Both IV and SC anakinra are safe in infants and children with acute Kawasaki disease and CAA. IV dosing every 8-12 hours during the acute hospitalization of patients with Kawasaki disease may result in a sustained concentration while avoiding frequent SC injections. The efficacy of a short course of IV therapy during hospitalization should be studied. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT02179853.

Safety, Tolerability, and Pharmacokinetics of a Long-Acting Broadly Neutralizing Human Immunodeficiency Virus Type 1 (HIV-1) Monoclonal Antibody VRC01LS in HIV-1-Exposed Newborn Infants.

BACKGROUND: Perinatal human immunodeficiency virus type 1 (HIV-1) continues to occur due to barriers to effective antiretroviral prevention that might be mitigated by long-acting broadly neutralizing monoclonal antibodies (bNAbs). METHODS: An extended half-life bNAb, VRC01LS, was administered subcutaneously at 80 mg/dose after birth to HIV-1-exposed, nonbreastfed (cohort 1, n = 10) and breastfed (cohort 2, n = 11) infants. Cohort 2 received a second dose (100 mg) at 12 weeks. All received antiretroviral prophylaxis. VRC01LS levels were compared to VRC01 levels determined in a prior cohort. RESULTS: Local reactions (all grade ≤2) occurred in 67% and 20% after dose 1 and dose 2, respectively. The weight-banded dose (mean 28.8 mg/kg) of VRC01LS administered subcutaneously achieved a mean (standard deviation) plasma level of 222.3 (71.6) µg/mL by 24 hours and 44.0 (11.6) µg/mL at week 12, prior to dose 2. The preestablished target of ≥50 µg/mL was attained in 95% and 32% at weeks 8 and 12, respectively. The terminal half-life was 37-41 days. VRC01LS level after 1 dose was significantly greater (P <.002) than after a VRC01 dose (20 mg/kg). No infants acquired HIV-1. CONCLUSIONS: VRC01LS was well tolerated with pharmacokinetics that support further studies of more potent long-acting bNAbs as adjunct treatment with antiretrovirals to prevent infant HIV-1 transmission.

Safety and Efficacy of Starting Antiretroviral Therapy in the First Week of Life.

BACKGROUND: Early antiretroviral therapy (ART) is recommended for infants with human immunodeficiency virus (HIV) infection. However, few antiretroviral options are available for neonates. METHODS: The Early Infant Treatment Study in Botswana tested HIV-exposed infants within 96 hours of birth, and HIV-infected infants started nevirapine (NVP) 6 mg/kg twice daily, zidovudine (ZDV), and lamivudine (3TC) at age < 7 days. NVP trough concentrations were tested at 1 and 2 weeks. NVP was switched to ritonavir-boosted lopinavir (LPV/r) at week 2, 3, 4, or 5 according to delivery gestational age. RESULTS: Forty HIV-infected infants started ART at median age 2 days (range, 1-5 days). NVP trough concentrations were highly variable and below therapeutic target (3000 ng/mL) for 50% of 2-week measurements; concentrations did not correlate with viral decline at weeks 2, 4, or 12. Two deaths unrelated to ART occurred through 24 weeks. Only 1 unscheduled treatment modification was required. Within 4 weeks of transition to LPV/r, 9 (22.5%) had transient HIV RNA increases, likely due to poor LPV/r palatability. At 12 weeks, 22 (55%) of 40 were <40 copies/mL (93% <400 copies/mL); by 24 weeks, 27 of 38 (71%) were < 40 copies/mL (84% < 400 copies/mL). HIV-1 RNA response at 12 and 24 weeks did not differ by baseline HIV RNA or other factors. CONCLUSIONS: NVP/ZDV/3TC started in the first week of life was safe and effective, even when trough NVP levels were below target. Transient viral increases occurred following transition to LPV/r, but by 12 and 24 weeks most children achieved and maintained viral suppression. CLINICAL TRIALS REGISTRATION: NCT02369406.

Population Pharmacokinetics of Tenofovir in Pregnant and Postpartum Women Using Tenofovir Disoproxil Fumarate.

Pharmacokinetics of drugs can be affected by physiologic changes during pregnancy. Our aim was to assess the influence of covariates on tenofovir (TFV) pharmacokinetics in pregnant and postpartum women receiving tenofovir disoproxil fumarate (TDF). Population pharmacokinetic parameter estimates and the influence of covariates were assessed using nonlinear mixed-effects modeling (NONMEM 7.4). Forty-six women had intensive pharmacokinetic evaluations during the second and third trimesters of pregnancy, with another evaluation postpartum. A two-compartment pharmacokinetic model with allometric scaling for body weight and first-order absorption best described the tenofovir plasma concentration data. Apparent oral clearance (CL/F) and volume of distribution at steady state (Vss/F) were increased during pregnancy. Weight, serum creatinine (SCr), pregnancy, albumin, and age were associated with TFV CL/F during univariate assessment, but in the multivariate analysis, changes in CL/F and Vss/F were only associated with increased body weight and enhanced renal function. Due to greater weight and lower SCr during pregnancy, CL/F was 28% higher during pregnancy than postpartum. In the final model, CL/F (liters per hour) was described as 2.07 × (SCr/0.6)0.65 × weight0.75, with a low between-subject variability (BSV) of 24%. The probability of target attainment (proportion exceeding area under the concentration-time curve of >1.99 µg·h/ml, the 10th percentile of average TFV exposure for nonpregnant historical controls) was 68%, 80%, 87%, and 93% above the target with 300 mg, 350 mg, 400 mg, and 450 mg of TDF, respectively, during pregnancy and 88%, 92%, 96%, and 98% above the target with same doses in postpartum women. Dose adjustment of TDF during pregnancy is not generally warranted, but any modification should be based on weight and renal function. (This study has been registered at ClinicalTrials.gov under identifier NCT00042289.).

S-warfarin limited sampling strategy with a population pharmacokinetic approach to estimate exposure and cytochrome P450 (CYP) 2C9 activity in healthy adults.

PURPOSE: S-warfarin is used to phenotype cytochrome P450 (CYP) 2C9 activity. This study evaluated S-warfarin limited sampling strategy with a population pharmacokinetic (PK) approach to estimate CYP2C9 activity in healthy adults. METHODS: In 6 previously published studies, a single oral dose of warfarin 10 mg was administered alone or with a CYP2C9 inducer to 100 healthy adults. S-warfarin concentrations were obtained from adults during conditions when subjects were not on any prescribed medications. A population PK model was developed using non-linear mixed effects modeling. Limited sampling models (LSMs) using single- or 2-timepoint concentrations were compared with full PK profiles from intense sampling using empiric Bayesian post hoc estimations of S-warfarin AUC derived from the population PK model. Preset criterion for LSM selection and validation were a correlation coefficient (R2) >0.9, relative percent mean prediction error (%MPE) >-5 to <5%, relative percent mean absolute error (%MAE) ≤ 10%, and relative percent root mean squared error (%RMSE) ≤ 15%. RESULTS: S-warfarin concentrations (n=2540) were well described with a two-compartment model. Mean apparent oral clearance was 0.56 L/hr and volume of distribution was 35.5 L. Clearance decreased 33% with the CYP2C9 *3 allele and increased 42% with lopinavir/ritonavir co-administration. During CYP2C9 constitutive conditions, LSMs at 48 hr and at 72 hr as well as 2-timepoint LSMs were within acceptable limits for R2, %MPE, %MAE, and %RMSE. During CYP2C9 induction, S-warfarin LSMs had unacceptable %MPE, %MAE, and %RMSE. CONCLUSIONS: Phenotyping studies with S-warfarin in healthy subjects can utilize a single- and/or a 2-timepoint LSM with a population PK approach to estimate constitutive CYP2C9 activity.

Lopinavir and tenofovir interaction observed in non-pregnant adults altered during pregnancy.

WHAT IS KNOWN AND OBJECTIVE: Tenofovir exposure is increased in non-pregnant adults when tenofovir disoproxil fumarate is coadministered with lopinavir/ritonavir. In pregnant women, tenofovir exposure is decreased. Our objective is to describe the effect of lopinavir/ritonavir on tenofovir pharmacokinetics during pregnancy. METHODS: Data were collected through the International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) Network P1026s protocol. This was a nonrandomized, open-label, parallel-group and multicentre phase-IV prospective study in pregnant women with HIV. Intensive steady-state 24-h pharmacokinetic profiles were collected during the third trimester of pregnancy and postpartum. Tenofovir was measured in plasma using validated liquid chromatography-mass spectrometry method (quantification limit: 10 ng/ml). Statistical tests compared paired and between group pharmacokinetic data. RESULTS AND DISCUSSION: In women not receiving lopinavir/ritonavir (n = 28), tenofovir AUC0-24 was 27% lower (2.2 mcg·h/ml vs 2.8 mcg·h/ml, p = 0.002) and oral clearance was 27% higher (61 L/h vs 48 L/h, p = 0.001) during the third trimester compared to paired postpartum data. In women receiving lopinavir/ritonavir (n = 10), tenofovir AUC0-24 and oral clearance were not different antepartum compared to postpartum. Women with and women without concomitant lopinavir/ritonavir displayed no significant differences in postpartum tenofovir pharmacokinetics. WHAT IS NEW AND CONCLUSION: Tenofovir exposure during the third trimester was reduced compared to postpartum in pregnant women not receiving lopinavir/ritonavir, but not in pregnant women also receiving lopinavir/ritonavir. Our findings suggest that pregnancy confounds the expected decrease in tenofovir exposure with concomitant lopinavir/ritonavir in non-pregnant adults. These findings illustrate the need for drug-drug interaction studies in pregnant women as drug disposition differs significantly in pregnant women compared to non-pregnant adults.

Safety, Tolerability, and Pharmacokinetics of the Broadly Neutralizing Human Immunodeficiency Virus (HIV)-1 Monoclonal Antibody VRC01 in HIV-Exposed Newborn Infants.

BACKGROUND: Although mother-to-child human immunodeficiency virus (HIV) transmission has dramatically decreased with maternal antiretroviral therapy, breast milk transmission accounts for most of the 180 000 new infant HIV infections annually. Broadly neutralizing antibodies (bNAb) may further reduce transmission. METHODS: A Phase 1 safety and pharmacokinetic study was conducted: a single subcutaneous (SC) dose of 20 or 40 mg/kg (Dose Groups 1 and 2, respectively) of the bNAb VRC01 was administered to HIV-exposed infants soon after birth. Breastfeeding infants (Dose Group 3) received 40 mg/kg SC VRC01 after birth and then 20 mg/kg/dose SC monthly. All infants received appropriate antiretroviral prophylaxis. RESULTS: Forty infants were enrolled (21 in the United States, 19 in Africa). Subcutaneous VRC01 was safe and well tolerated with only mild-to-moderate local reactions, primarily erythema, which rapidly resolved. For multiple-dose infants, local reactions decreased with subsequent injections. VRC01 was rapidly absorbed after administration, with peak concentrations 1-6 days postdose. The 40 mg/kg dose resulted in 13 of 14 infants achieving the serum 50 micrograms (mcg)/mL target at day 28. Dose Group 3 infants maintained concentrations greater than 50 mcg/mL throughout breastfeeding. CONCLUSIONS: Subcutaneous VRC01 as single or multiple doses is safe and well tolerated in very young infants and is suitable for further study to prevent HIV transmission in infants.

Population Pharmacokinetics of Praziquantel in Pregnant and Lactating Filipino Women Infected with Schistosoma japonicum.

An estimated 40 million women of reproductive age are infected with one of three species of the waterborne parasite Schistosoma spp. Treatment with praziquantel (PZQ) via mass drug administration (MDA) campaigns is the mainstay of schistosomiasis control for populations living in areas of endemicity. The World Health Organization recommends that pregnant and lactating women be included in schistosomiasis MDA programs, and several recent studies have evaluated the safety and efficacy of PZQ use during pregnancy. To date, there are no data describing PZQ pharmacokinetics (PK) during pregnancy or among lactating postpartum women. As part of a randomized controlled trial investigating the safety and efficacy of PZQ during human pregnancy, we examined the PK of this therapeutic drug among three distinct cohorts of women infected with S. japonicum in Leyte, Philippines. Specifically, we studied the PK properties of PZQ among early- and late-gestation pregnant women (n = 15 each) and lactating postpartum women (n = 15) with schistosomiasis. We found that women in early pregnancy had increased apparent clearance and lower area-under-the-curve (AUC0-24) values that may be related to physiological changes in drug clearance and/or changes in oral bioavailability. There was no relationship between body weight and apparent clearance. The mean ± standard deviation partition ratio of plasma to breast milk was 0.36. ± 0.13. The estimated median infant PZQ daily dose would be 0.037 mg/kg of body weight ingested from breast milk, which is significantly lower than the dosage required for antischistosomal activity and not known to be harmful to the infant. Our PK data do not support the suggestion to delay breastfeeding 72 h after taking PZQ. Results can help inform future drug efficacy studies in pregnant and lactating women with schistosomiasis.

Fosamprenavir with Ritonavir Pharmacokinetics during Pregnancy.

The purpose of this study was to evaluate the pharmacokinetics of ritonavir-boosted fosamprenavir during pregnancy and postpartum. Amprenavir (the active moiety of fosamprenavir) and ritonavir intensive pharmacokinetic evaluations were performed at steady state during the second and third trimesters of pregnancy and postpartum. Plasma concentrations of amprenavir and ritonavir were measured using high-performance liquid chromatography. The target amprenavir area under the concentration-versus-time curve (AUC) was higher than the 10th percentile (27.7 µg · h/ml) of the median area under the curve for ritonavir-boosted fosamprenavir in adults receiving twice-daily fosamprenavir-ritonavir at 700 mg/100 mg. Twenty-nine women were included in the analysis. The amprenavir AUC from time zero to 12 h (AUC0-12) was lower (geometric mean ratio [GMR], 0.60 [confidence interval {CI}, 0.49 to 0.72] [P < 0.001]) while its apparent oral clearance was higher (GMR, 1.68 [CI, 1.38 to 2.03] [P < 0.001]) in the third trimester than postpartum. Similarly, the ritonavir AUC0-12 was lower in the second (GMR, 0.51 [CI, 0.28 to 0.91] [P = 0.09]) and third (GMR, 0.72 [CI, 0.55 to 0.95] [P = 0.005]) trimesters than postpartum, while its apparent oral clearance was higher in the second (GMR, 1.98 [CI, 1.10 to 3.56] [P = 0.06]) and third (GMR, 1.38 [CI, 1.05 to 1.82] [P = 0.009]) trimesters than postpartum. The amprenavir area under the curve exceeded the target for 6/8 (75%) women in the 2nd trimester, 18/28 (64%) in the 3rd trimester, and 19/22 (86.4%) postpartum, and the trough concentrations (Cmin) of amprenavir were 4- to 16-fold above the mean amprenavir-protein-adjusted 50% inhibitory concentration (IC50) of 0.146 µg/ml. Although amprenavir plasma concentrations in women receiving ritonavir-boosted fosamprenavir were lower during pregnancy than postpartum, the reduced amprenavir concentrations were still above the exposures needed for viral suppression.