Children have distinct therapeutic needs arising from age-dependent physiology, disease epidemiology, formulation requirements, dosing considerations, and safety vulnerabilities. Despite substantial reductions in childhood mortality over the past three decades, nearly 5 million children under five died in 2023, with infectious diseases continuing to contribute substantially to preventable morbidity and mortality. Long-acting therapeutics (LATs) may help address selected pediatric health priorities by sustaining therapeutic or prophylactic exposure, reducing dosing frequency, and improving adherence and implementation feasibility. This review synthesizes insights from the pediatric health session of the Community of Practice for Long-acting Therapeutics for Maternal and Paediatric Health workshop. The session considered priority pediatric conditions in which existing or emerging LAT approaches could have clinical or public health impact, including lower respiratory tract infections, malaria, tuberculosis, HIV, and syphilis, as well as selected noninfectious indications such as childhood cancer and growth hormone deficiency. We then examine clinical pharmacology and safety considerations central to pediatric LAT development, including developmental pharmacokinetics, absorption-limited disposition and flip-flop kinetics, pharmacokinetic tailing, dose selection, model-informed development, and injection-site tolerability. The review also discusses long-acting technology platforms with potential pediatric applications, route-of-administration considerations, excipient safety, formulation design, acceptability, and implementation challenges. Finally, we propose recommendations to support pediatric LAT development, including early integration of developmental pharmacology, age- and weight-informed dosing, standardized acceptability assessment, product-attribute frameworks, regulatory engagement, and equitable access planning. Realizing the potential of LATs for children will require coordinated, child-centered, and equity-driven approaches that address evidence generation, formulation suitability, implementation context, and affordability from the outset.

ABSTRACT Staphylococcus aureus increasingly causes late-onset neonatal sepsis with mortality ≤25%. Oxacillin treats methicillin-susceptible Staphylococcus aureus (MSSA). No previous studies inform dosing. Time above MIC of unbound oxacillin ( f T>MIC) 100% of dosing interval is a desired pharmacodynamic (PD) target in immunocompromised/septic patients. Our objective was to characterize oxacillin pharmacokinetics (PK) and PD in young infants. We conducted a prospective PK/PD study in infants ≤90 days. We divided four cohorts per gestational (GA <32/≥32 weeks) and postnatal age (PNA <14/≥14 days). Patients received 25 mg/kg loading doses followed by continuous infusions of 120 (<32 weeks/<14 days) or 160 mg/kg/day. Population PK parameters were estimated using NONMEM. Dosing regimens were evaluated using Monte Carlo simulations to estimate the probability of PD target attainment. Outcomes were collected. We enrolled 22 infants, median (IQR) GA 38 weeks (30–39) and PNA 32 days (12–46). PNA and weight were covariates for oxacillin clearance. Unbound steady-state oxacillin concentrations remained >MIC 0.5 throughout the dosing interval for >90% of modeled patients for all age groups on 160 mg/kg/day continuous infusions. Infants with PNA ≤28 days met PD targets at MIC 1; <90% of all modeled patients on continuous infusion met PD targets at MIC 2. Modeled infants receiving 200 mg/kg/day oxacillin divided q4h/q6h failed to meet PD targets up to MIC 2. All patients survived to discharge. A few serious adverse events were noted. 160 mg/kg/day continuous oxacillin was well tolerated and achieved PD targets for MIC ≤0.5 across all age groups. Modeled intermittent dosing ≤200 mg/kg/day divided q4h/q6h, 8 times the Food and Drug Administration-labeled dose of 25 mg/kg daily, failed to achieve PD targets. The FDA-recommended oxacillin dose is inadequate and may help explain high mortality.

Meropenem dosing to achieve therapeutic exposure in critically ill children with sepsis is challenging due to a spectrum of renal function, from augmented renal clearance (ARC) to acute kidney injury (AKI). The objective of this study was to define meropenem plasma concentrations and pharmacodynamic exposure metrics in children with septic shock during the first 3 days of PICU hospitalization. We prospectively evaluated meropenem clearance (CLMERO) and volume of distribution (V1-MERO), innovatively assessing renal biomarkers (serum creatinine [SCr], serum cystatin C [SCys], and neutrophil gelatinase-associated lipocalin [SNgal]), in infants aged ≥ 4 weeks and children on intravenous (IV) meropenem 20 mg/kg every 8 h from 2019 to 2023. Cases with sepsis were matched to controls without sepsis. Analysis included 27 participants (19 cases and 8 controls) with 309 meropenem serum concentrations. Median age was 11.8 (range 0.6–19.6) years, weight 36.3 (7.2–98.0) kg, SCr 0.33 (0.09–2.57) mg/dL, SCys 451.1 (178.3–1824.1) ng/mL, and SNgal 180.7 (23.2–1403.0) ng/mL. A 2-compartment, population pharmacokinetic (PK) model via NONMEM best described data, with weight on VMERO and allometric scaling on CLMERO. Using the final model with SCys in V1-MERO and estimated glomerular filtration rate (eGFR)-MS in CLMERO, the median V1-MERO was 0.23 (range 0.07–0.57) L/kg and CLMERO 0.15 (0.05–0.49) L/h/kg, with eGFR–MS 139 (23–365) mL/min/1.73 m2 from AKI to ARC. Meropenem clearance, V1-MERO and eGFR-MS were significantly decreased in cases versus controls, with higher variability of eGFR-MS in cases. Wide variation in meropenem concentrations in children with sepsis as compared to those without sepsis prompt close monitoring of GFR and drug concentrations in this population.

BACKGROUND:Dolutegravir is not recommended for neonates (age 28 days or younger) due to the absence of dosing guidelines and safety information. We evaluated the multidose pharmacokinetics and safety of two paediatric dolutegravir formulations in neonates: a scored dispersible tablet and a novel oral dispersible film. METHODS:We did a phase 1/2, open-label, single-centre, two-stage, randomised trial in neonates at Tygerberg Hospital, South Africa, who were born at term (≥37 weeks gestational age, birthweights ≥2 kg) to pregnant women on dolutegravir-based antiretroviral therapy. Neonates in stage two were randomly assigned (1:1) to receive 5 mg dolutegravir either as half of a scored dispersible tablet (10 mg) or one oral dispersible film (5 mg), administered every 48 h for the first 2 weeks of life, followed by daily up to day 28 of life. Plasma pharmacokinetic samples were collected during three visits: at entry (before and 1-3 h after the first dolutegravir dose); at any time from the third dolutegravir dose but before week 4 of life (before and 1, 2, 4, 6, and 48 h after the dolutegravir dose); and during week 4 of life (before and 1-3 h after the dolutegravir dose). The primary outcomes were dolutegravir pharmacokinetic parameters of area under the concentration time curve (AUC), maximum plasma concentration (Cmax), apparent clearance (CL/F), and trough concentration (Ctrough) in participants who completed intensive pharmacokinetic sampling and occurrence of non-treatment-related and treatment-related adverse events of grade 3 or higher and any adverse events in participants who received at least one dose of dolutegravir. Target pharmacokinetic criteria were geometric mean Ctrough higher than 0·67 μg/mL and individual Cmax lower than 17·0 μg/mL. The trial is registered with ClinicalTrials.gov, NCT05590325. FINDINGS:Between Sept 15, 2023, and Nov 6, 2024, 41 neonates were enrolled, randomly assigned, and received dolutegravir (21 [51%] received dispersible tablets and 20 [49%] received dolutegravir films); 25 (61%) neonates were male and 16 (39%) were female. Median birthweight was 3235 g (range 2365-4330) and the first dolutegravir dose was administered at median 47 h (range 22-78) after birth. Intensive dolutegravir pharmacokinetic profiles sampled after at least three doses of dolutegravir (range 6-10 days of life) were similar between the dolutegravir dispersible tablet and the dolutegravir film and the dolutegravir geometric mean area under the concentration time curve (AUC0-48), and CL/F were 193·2 μg x h/mL and 0·026 L/h, respectively. Both formulations attained a dolutegravir geometric mean Ctrough higher than 0·67 μg/mL. All neonates had a dolutegravir Cmax lower than 17·0 μg/mL at every pharmacokinetic visit. No adverse events were related to dolutegravir. Two grade 3 adverse events, the highest severity observed, occurred in one neonate with pneumonia. A total of 22 adverse events occurred in 12 (57%) of the 21 neonates receiving dolutegravir dispersible tablets and 23 adverse events occurred in 14 (70%) of the 20 neonates receiving dolutegravir films. All 39 neonates who completed follow-up were HIV negative at study exit. INTERPRETATION:To our knowledge, this is the first evidence providing dolutegravir dosing guidance from birth up to week 4 of life, supporting inclusion into national and international antiretroviral dosing guidelines. FUNDING:Unitaid.

Objectives: To define meropenem plasma concentrations and pharmacodynamic exposure metrics in children with septic shock during the first 3 days of PICU hospitalization. Design: Pharmacokinetic sampling was undertaken in 19 subjects receiving standard meropenem dosing (20 mg/kg/dose, 8 hr) recruited from March 2019 to March 2022. Sampling occurred once each day following meropenem given 24 hours apart, during the first 3 PICU days. Data analysis was completed in 2023 and noncompartmental analysis was performed to assess pharmacodynamic exposure targets for sepsis. Clearance and volume of distribution at 20 mg/kg/dose were used to simulate mean exposures at 40 and 60 mg/kg/dose. Setting: PICU in a tertiary care center. Subjects: Patients 4 weeks old or older with hypotension requiring fluid resuscitation and vasopressor therapy, receiving meropenem as empiric therapy for sepsis. Interventions: None. Measurements and Main Results: Augmented renal clearance (ARC) was documented in eight of 19 subjects, previously associated with subtherapeutic plasma concentrations, while three of 19 had acute kidney injury and decreased renal clearance. When assessed by pharmacodynamic exposure targets for sepsis (plasma meropenem concentrations above the minimum inhibitory concentration [MIC] of Pseudomonas aeruginosa for 70% or 100% of the dosing interval), ten of 19 and nine of 19 children, respectively, had subtherapeutic plasma meropenem exposures during PICU day 1, even for pathogens with an MIC considered “susceptible” by U.S. Food and Drug Administration criteria. Therapeutic meropenem pharmacodynamic exposures were associated with a positive 24-hour fluid balance on PICU day 1 and a negative 24-hour fluid balance by day 3, although profound variability was noted in fluid administered and renal output. Conclusions: Given the variability in meropenem systemic exposure in pediatric septic shock, therapeutic drug monitoring, or monitoring for ARC, is suggested during the first days of hospitalization to allow daily assessments of dosing needs to achieve pharmacodynamic exposure targets for sepsis.

BACKGROUND:Long-acting cabotegravir and long-acting rilpivirine constitute a completely intramuscular antiretroviral therapy (ART) regimen for adults with HIV. We aimed to assess the safety, antiviral activity, and pharmacokinetics of oral cabotegravir and rilpivirine followed by a combination of long-acting cabotegravir and long-acting rilpivirine in virologically suppressed adolescents with HIV. METHODS:The IMPAACT 2017/MOCHA study is a phase 1/2, multicentre, open-label, non-comparative, dose-finding trial being conducted at 18 sites across Botswana, South Africa, Thailand, Uganda, and the USA. In cohort 2 of this study, adolescents (aged 12-18 years; weight ≥35 kg) with HIV and no serious comorbidities who were receiving stable combination ART with confirmed virological suppression and had either previously enrolled in the first cohort or had not previously participated in the study were eligible for inclusion. Participants stopped their background combination ART and received oral cabotegravir 30 mg once daily and oral rilpivirine 25 mg once daily orally for 4-6 weeks, followed by long-acting injectable cabotegravir 600 mg (3 mL) and long-acting injectable rilpivirine 900 mg (3 mL) intramuscularly at weeks 4 and 8, and every 8 weeks thereafter. The primary outcome was safety, including all adverse events, at week 24. Primary safety outcome measures were summarised as frequencies, percentages, and exact Clopper-Pearson 95% CIs in the evaluable analysis population, which included participants who were treated exclusively with the regimen and either completed all scheduled treatments or experienced severe adverse events, permanently discontinued the treatment, or died, whichever occurred first; and in the all-treated analysis population, which included all participants who received at least one dose of any study product. This study is registered with ClinicalTrials.gov (NCT3497676) and is ongoing. FINDINGS:Between July 26, 2021, and Aug 27, 2022, 44 (80·0%) of 55 adolescents who participated in cohort 1 and 100 (87·0%) of 115 screened study-naive adolescents were enrolled in cohort 2. 74 (51·4%) participants were female and 70 (48·6%) were male. Overall, 15 (10·8% [95% CI 6·2-17·2]) of all 139 participants in the evaluable analysis population had at least one adverse event of grade 3 or above by week 24. Among 142 participants who received at least one injection, 43 (30%) experienced at least one injection site reaction (ISR). All 106 ISRs were either grade 1 (98 [92·5%]) or grade 2 (eight [7·5%]), and 97 (91·5%) resolved within 7 days. No participant experienced a drug-related serious adverse event or prematurely discontinued treatment due to a drug-related adverse event. INTERPRETATION:Long-acting injectable cabotegravir and long-acting injectable rilpivirine, administered to adolescents at recommended adult dosages every 8 weeks, showed no unanticipated safety concerns in the 24 weeks following administration. FUNDING:National Institutes of Health, ViiV Healthcare, and Johnson & Johnson.

BACKGROUND:We hypothesised that initiating antiretroviral therapy (ART) soon after birth could limit HIV-1 reservoirs and promote ART-free remission. This study aims to assess remission in children with in-utero HIV-1 infection who received very early ART as neonates by performing analytical treatment interruption (ATI). METHODS:IMPAACT P1115 is an ongoing, open-label, proof-of-concept study at 30 research sites in 11 countries across Africa, Asia, and the Americas. Neonates (≥34 weeks gestational age) at high risk for in-utero HIV-1 were eligible. Neonates born to mothers with untreated HIV-1 (cohort 1) or mothers who might have been on ART (cohort 2) initiated three-drug oral nevirapine-based ART (6mg/kg per dose orally twice a day) within 48 h of birth (cohort 1), three-drug nevirapine-based prophylaxis (≥8 mg/kg per dose orally once a day), or nevirapine-based ART after HIV-1 diagnosis by age 10 days (cohort 2). Coformulated ritonavir 75 mg/m2 and lopinavir 300 mg/m2 orally twice a day was added when age appropriate for those with confirmed in-utero HIV-1. Nevirapine was discontinued 12 weeks after two consecutive plasma viral loads were below the assay limit. Children at least 2 years of age maintaining undetectable HIV-1 RNA since week 48 and who tested HIV-1 antibody negative, HIV-1 DNA not detected, and normal CD4 count and percentage qualified for ATI. The primary outcome was ART-free remission, defined as no HIV-1 RNA in plasma for 48 weeks or more off ART. A two-sided exact 95% CI was calculated to estimate the probability of remission. This study is registered with ClinicalTrials.gov (NCT02140255). FINDINGS:Among 54 children with in-utero HIV-1 enrolled between Jan 23, 2015, and Dec 14, 2017, six (11%) children (four girls, two boys; one in cohort 1, five in cohort 2) met criteria and underwent ATI at a median age of 5·5 years. Two children had early rebound at 3·4 weeks and 9·4 weeks. Four reached ART-free remission (67%; exact 95% CI 22-96), one of whom had late viral rebound at 79·3 weeks. All three children with viral rebound successfully resuppressed HIV-1 RNA below the assay limit on ART. Mild symptoms of acute retroviral syndrome occurred in two participants during rebound and resolved with ART resumption. INTERPRETATION:This study shows that ART-free remission for 48 weeks or longer is achievable with very early ART in children with in-utero HIV-1, but close monitoring for viral rebound and acute retroviral syndrome during ATI is needed. These findings, observed in resource-constrained countries, exhibit the feasibility of testing at birth and initiating very early ART, show the potential to limit HIV-1 reservoirs for ART-free remission, and inform future remission strategies. FUNDING:The US National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the US National Institute of Mental Health.

BACKGROUND. HIV-1-specific broadly neutralizing monoclonal antibodies (bNAbs) have emerged as promising interventions with the potential to effectively treat and prevent HIV-1 infections. We conducted a phase I clinical trial evaluating the potent CD4-binding site-specific (CD4bs-specific) bNAbs VRC01LS and VRC07-523LS in people with HIV-1 (PWH) not receiving antiretroviral therapy (ART). METHODS. Participants received a single intravenous 40 mg/kg dose of either VRC01LS (n = 7) or VRC07-523LS (n = 9) and did not initiate ART for a minimum of 14 days. The primary study objective was to evaluate safety and tolerability; the secondary study objectives were to evaluate pharmacokinetics (PK) and the impact of administered bNAbs on viral loads (VL) and CD4(+) T cell counts in the absence of ART. RESULTS. This trial enrolled 16 PWH aged 20 to 57 years. Both bNAbs were safe and well tolerated. Mild local reactogenicity was only reported in participants who received VRC07-523LS, while both bNAbs were associated with mild systemic symptoms. Maximum serum concentrations (C-max) following VRC01LS or VRC07-523LS were 1,566 +/- 316 and 1,295 +/- 376 mu g/mL, respectively. VRC07-523LS administration significantly decreased VL in 8 out of 9 participants, with an average decline of 1.7 +/- 0.8 log(10) copies/mL within 14 days after administration. In contrast, VRC01LS administration resulted in a smaller average decline (0.8 +/- 0.8 log(10) copies/mL), and 3 out of 7 participants showedno change in VL. Postinfusion maximum decline in VL correlated with post hoc baseline in vitro viral susceptibility results for both bNAbs. CONCLUSION. The results of this trial support inclusion of potent CD4bs-specific bNAbs, such as VRC07-523LS, into next-generation treatment regimens for HIV-1. TRIAL REGISTRATION. ClinicalTrials.gov NCT02840474.

Background: Dolutegravir dispersible tablets (DTG-DT) are approved for infants ≥4 weeks and ≥3 kg but their suitability for neonates remains unknown. Methods: PETITE-DTG is a Phase I/II, open-label, single center, two-stage trial in South Africa to evaluate the pharmacokinetics (PK) and safety of DTG in term neonates of pregnant individuals receiving DTG-based therapy. In Stage 1, neonates on standard antiretroviral prophylaxis received a single dose of 5 mg DTG-DT between ≥14 and <28 days of life (Cohort 1A); or <14 days of life (Cohort 1B), followed by PK and safety assessments. A population PK model was developed and multi-dose scenarios simulated [DTG targets: geometric mean (GM) C tau >0.67 µg/mL and C max <17.0 µg/mL]. Results: 16 neonates, 8 per cohort, completed Stage 1. Median (range) birth weight was 3.1 (2.6-4.2) kg and PK sampling was performed between 3-22 days of life. No Grade 3 or higher adverse events were observed. DTG clearance was influenced by body weight and postnatal age. Simulations predicted that >10% of neonates would have a C max >17.0 µg/mL with DTG once daily (q24) during the first 2 weeks of life. Administration of DTG every 48 hours (q48) from day 1-14 of life, followed by DTG every 24 hours through day 28, predicted a GM C tau between 0.86-4.35 µg/mL; 98% with a C max <17.0 µg/mL. Conclusions: Due to the slow postnatal DTG clearance after birth, a multi-dose strategy of 5 mg DTG-DT q48 for the first 2 weeks of life, followed by q24 through 28 days, was selected for assessment in Stage 2.

After sporadic reports of post-treatment control of HIV in children who initiated combination anti-retroviral therapy (cART) early, we prospectively studied 284 very-early-cART-treated children from KwaZulu-Natal, South Africa, after vertical HIV transmission to assess control of viremia. Eighty-four percent of the children achieved aviremia on cART, but aviremia persisting to 36 or more months was observed in only 32%. We observed that male infants have lower baseline plasma viral loads (P = 0.01). Unexpectedly, a subset (n = 5) of males maintained aviremia despite unscheduled complete discontinuation of cART lasting 3-10 months (n = 4) or intermittent cART adherence during 17-month loss to follow-up (n = 1). We further observed, in vertically transmitted viruses, a negative correlation between type I interferon (IFN-I) resistance and viral replication capacity (VRC) (P < 0.0001) that was markedly stronger for males than for females (r = -0.51 versus r = -0.07 for IFN-alpha). Although viruses transmitted to male fetuses were more IFN-I sensitive and of higher VRC than those transmitted to females in the full cohort (P < 0.0001 and P = 0.0003, respectively), the viruses transmitted to the five males maintaining cART-free aviremia had significantly lower replication capacity (P < 0.0001). These data suggest that viremic control can occur in some infants with in utero-acquired HIV infection after early cART initiation and may be associated with innate immune sex differences.

BACKGROUND:Vertical HIV-1 transmission despite antiretroviral therapy may be mitigated by the use of long-acting, broadly neutralizing, monoclonal antibodies (bNAb) such as VRC07-523LS. The present study was designed to determine the safety and pharmacokinetics of VRC07-523LS. METHODS:VRC07-523LS, 80 mg/dose, was administered subcutaneously after birth to non-breastfed (cohort 1; N = 11, enrolled in USA) and breastfed (cohort 2; N = 11, enrolled in South Africa and Zimbabwe) infants exposed to HIV-1. Breastfed infants (cohort 2) received a second 100-mg dose at 12 weeks if still receiving breastmilk. All infants received antiretroviral prophylaxis in addition to VRC07-523LS. VRC07-523LS levels were compared to VRC01 levels, as determined previously in this study. RESULTS:Local reactions (all grade ≤ 2) occurred after dose 1 in 18% of infants in cohort 1 and after doses 1 and 2 in 100% of infants in cohort 2. The VRC07-523LS dose at birth (mean 26 mg/kg) achieved a mean ± SD plasma level of 222.3 ± 71.6 mcg/mL by 24 hours and 18.4 ± 7.2 mcg/mL at week 12, prior to dose 2. The pre-established target of ≥ 10 mcg/mL at week 12 was met in 94% of infants. The terminal half-life of VRC07-523LS was observed to be 39.2 ± 5.0 days. At week 4 and week 8, bNAb levels were significantly higher (P ≤ .002) after one dose of VRC07-523LS, compared to one dose of VRC01 (20 mg/kg). No infant included in the study acquired HIV-1. CONCLUSIONS:VRC07-523LS was well tolerated with pharmacokinetics that support further studies of potent long-acting bNAbs together with antiretrovirals to prevent HIV-1 acquisition in infants.

The pharmacokinetics (PK) of antituberculosis drugs may be altered by both pregnancy-induced physiological changes and drug interactions in individuals living with HIV who develop tuberculosis. Within the multicenter International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s study, we assessed the PK of rifampin, isoniazid, ethambutol, and pyrazinamide during pregnancy and postpartum (PP) in women on efavirenz-based antiretroviral therapy (ART). Results were compared to a previously published non-HIV group and described minimum targets. World Health Organization-recommended daily doses of antituberculosis and ART medications were administered, followed by PK sampling of all antituberculosis drugs over 24 h during the second trimester (2T), third trimester (3T), and 2-8 weeks PP. PK parameters were characterized using noncompartmental analysis, and comparisons were made among stages of pregnancy and between groups using geometric mean ratios with 90% confidence intervals. Twenty-two participants were enrolled, and PK data were available for 12, 20, and 13 participants in 2T, 3T, and PP, respectively. While no significant difference in rifampin exposure between pregnancy and postpartum was detected, the median area-under-the-plasma-concentration-time-curve up to 24 h post-dose (AUC0-24) and Cmax were below target during each period and were 42% and 35% lower in 3T than the non-HIV group. No significant difference in isoniazid exposure was found between pregnancy and PP or between the groups. Ethambutol and pyrazinamide AUC0-24 and Cmax in 2T and 3T were similar between the groups. In both groups, pyrazinamide Cmax was above target in all periods. The clinical relevance of lower rifampin exposure in pregnant women requiring tuberculosis treatment while on efavirenz should be determined.

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 mu g/mL and 56.6% would exceed the observed adult lower limit of LPV exposure of 55.9 mu gh/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.

Background Existing solid antiretroviral fixed-dose combination formulations are preferred over liquid formulations in children, but their suitability for neonates is unknown. We evaluated the pharmacokinetics and safety of paediatric abacavir-lamivudine fixed-dose dispersible tablets and ritonavir-boosted lopinavir granules in neonates. Methods In this open-label, two-stage, single-arm, phase 1/2, pharmacokinetic and safety trial, generic abacavir-lamivudine (120:60 mg) double-scored dispersible tablets and lopinavir boosted with ritonavir (40:10 mg) granules were studied. Neonates exposed to HIV (>= 37 weeks gestational age) of no more than 3 days of age with birthweights of 2000-4000 g were identified through routine care in a tertiary hospital in Cape Town, South Africa. In stage 1, the pharmacokinetics and safety of two single doses were assessed to select the multidose strategy for stage 2. Neonates received a single dose of abacavir-lamivudine (30:15 mg, a quarter of a tablet) and lopinavir boosted with ritonavir (40:10 mg - one sachet) orally between 3 days and 14 days of age, and a second dose of a quarter tablet of abacavir-lamivudine and lopinavir boosted with ritonavir (80:20 mg, two sachets) 10-14 days later in stage 1. The multidose strategy selected in stage 2 was a quarter of the abacavir-lamivudine (30:15 mg) fixed-dose dispersible tablet once per day and two sachets of the lopinavir boosted with ritonavir (80:20 mg) granules twice per day from birth to age 28 days. In both stages two intensive pharmacokinetic visits were done, one at less than 14 days of life (pharmacokinetics 1) and another 10-14 days later (pharmacokinetics 2). Safety visits were done 1-2 weeks after each pharmacokinetic visit. Primary objectives were to assess pharmacokinetics and safety of abacavir, lamivudine, and lopinavir. Pharmacokinetic endpoints were area under the concentration time curve (AUC), maximum concentration, and concentration at end of dosing interval in all participants with at least one evaluable pharmacokinetic visit. Safety endpoints included grade 3 or worse adverse events, and grade 3 or worse treatment-related adverse events, occurring between study drug initiation and end of study. This completed trial is registered with the Pan African Clinical Trials Registry (PACTR202007806554538). Findings Between Aug 18, 2021, and Aug 18, 2022, 24 neonates were enrolled into the trial and received study drugs. Eight neonates completed stage 1, meeting interim pharmacokinetic and safety criteria. In stage 2, 16 neonates received study drugs. Geometric mean abacavir and lamivudine exposures (AUC(0-24)) were higher at 6-14 days (51.7 mg x h/L for abacavir and 17.2 mg x h/L for lamivudine) than at 19-24 days of age (25.0 mg xh/L and 11.3 mg x h/L), whereas they were similar for lopinavir over this period (AUC 0-12 58.5 mg x h/L vs 46.4 mg x h/L). Abacavir geometric mean AUC0-24 crossed the upper reference range at pharmacokinetics 1, but rapidly decreased. Lamivudine and lopinavir AUC0-tau were within range. No grade 2 or worse adverse events were related to study drugs. One neonate had a grade 1 prolonged corrected QT interval using the Fridericia method that spontaneously resolved. Interpretation Abacavir-lamivudine dispersible tablets and ritonavir-boosted lopinavir granules in neonates were safe and provided drug exposures similar to those in young infants. Although further safety data are needed, this regimen presents a new option for HIV prevention and treatment from birth. Accelerating neonatal pharmacokinetic studies of novel antiretroviral therapies is essential for neonates to also benefit from state-of-the-art treatments. Copyright (C) 2024 Elsevier Ltd. All rights reserved.

BACKGROUND:Combined intramuscular long-acting cabotegravir and long-acting rilpivirine constitute the first long-acting combination antiretroviral therapy (ART) regimen approved for adults with HIV. The goal of the IMPAACT 2017 study (MOCHA [More Options for Children and Adolescents]) was to assess the safety and pharmacokinetics of these drugs in adolescents. METHODS:In this phase 1/2, multicentre, open-label, non-comparative, dose-finding study, virologically suppressed adolescents (aged 12-17 years; weight ≥35 kg; BMI ≤31·5 kg/m2) with HIV-1 on daily oral ART were enrolled at 15 centres in four countries (Botswana, South Africa, Thailand, and the USA). After 4-6 weeks of oral cabotegravir (cohort 1C) or rilpivirine (cohort 1R), participants received intramuscular long-acting cabotegravir or long-acting rilpivirine every 4 weeks or 8 weeks per the adult dosing regimens, while continuing pre-study ART. The primary outcomes were assessments of safety measures, including all adverse events, until week 4 for oral cabotegravir and until week 16 for long-acting cabotegravir and long-acting rilpivirine, and pharmacokinetic measures, including the area under the plasma concentration versus time curve during the dosing interval (AUC0-tau) and drug concentrations, at week 2 for oral dosing of cabotegravir and at week 16 for intramuscular dosing of cabotegravir and rilpivirine. Enrolment into cohort 1C or cohort 1R was based on the participant's pre-study ART, meaning that masking was not done. For pharmacokinetic analyses, blood samples were drawn at weeks 2-4 after oral dosing and weeks 4-16 after intramuscular dosing. Safety outcome measures were summarised using frequencies, percentages, and exact 95% CIs; pharmacokinetic parameters were summarised using descriptive statistics. This trial is registered at ClinicalTrials.gov, NCT03497676, and is closed to enrolment. FINDINGS:Between March 19, 2019, and Nov 25, 2021, 55 participants were enrolled: 30 in cohort 1C and 25 in cohort 1R. At week 16, 28 (97%, 95% CI 82-100) of the 29 dose-evaluable participants in cohort 1C and 21 (91%; 72-99) of the 23 dose-evaluable participants in cohort 1R had reported at least one adverse event, with the most common being injection-site pain (nine [31%] in cohort 1C; nine [39%] in cohort 1R; none were severe). One (4%, 95% CI 0-22) participant in cohort 1R had an adverse event of grade 3 or higher, leading to treatment discontinuation, which was defined as acute rilpivirine-related allergic reaction (self-limiting generalised urticaria) after the first oral dose. No deaths or life-threatening events occurred. In cohort 1C, the week 2 median cabotegravir AUC0-tau was 148·5 (range 37·2-433·1) μg·h/mL. The week 16 median concentrations for the every-4-weeks and every-8-weeks dosing was 3·11 μg/mL (range 1·22-6·19) and 1·15 μg/mL (<0·025-5·29) for cabotegravir and 52·9 ng/mL (31·9-148·0) and 39·1 ng/mL (27·2-81·3) for rilpivirine, respectively. These concentrations were similar to those in adults. INTERPRETATION:Study data support using long-acting cabotegravir or long-acting rilpivirine, given every 4 weeks or 8 weeks, per the adult dosing regimens, in virologically suppressed adolescents aged 12 years and older and weighing at least 35 kg. FUNDING:The National Institutes of Health and ViiV Healthcare.

BACKGROUNDBroadly neutralizing monoclonal antibodies (bNAbs) represent a promising strategy for HIV-1 immunoprophylaxis and treatment. 10E8VLS and VRC07-523LS are bNAbs that target the highly conserved membrane-proximal external region (MPER) and the CD4-binding site of the HIV-1 viral envelope glycoprotein, respectively.METHODSIn this phase 1, open-label trial, we evaluated the safety and pharmacokinetics of 5 mg/kg 10E8VLS administered alone, or concurrently with 5 mg/kg VRC07-523LS, via s.c. injection to healthy non-HIV-infected individuals.RESULTSEight participants received either 10E8VLS alone (n = 6) or 10E8VLS and VRC07-523LS in combination (n = 2). Five (n = 5 of 8, 62.5%) participants who received 10E8VLS experienced moderate local reactogenicity, and 1 participant (n = 1/8, 12.5%) experienced severe local reactogenicity. Further trial enrollment was stopped, and no participant received repeat dosing. All local reactogenicity resolved without sequelae. 10E8VLS retained its neutralizing capacity, and no functional anti-drug antibodies were detected; however, a serum t1/2 of 8.1 days was shorter than expected. Therefore, the trial was voluntarily stopped per sponsor decision (Vaccine Research Center, National Institute of Allergy and Infectious Diseases [NIAID], NIH). Mechanistic studies performed to investigate the underlying reason for the reactogenicity suggest that multiple mechanisms may have contributed, including antibody aggregation and upregulation of local inflammatory markers.CONCLUSION10E8VLS resulted in unexpected reactogenicity and a shorter t1/2 in comparison with previously tested bNAbs. These studies may facilitate identification of nonreactogenic second-generation MPER-targeting bNAbs, which could be an effective strategy for HIV-1 immunoprophylaxis and treatment.TRIAL REGISTRATIONClinicaltrials.gov, accession no. NCT03565315.FUNDINGDivision of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH.

Background Pregnant people with coronavirus disease 2019 (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 4 prospective, open-label, nonrandomized opportunistic study of hospitalized pregnant and nonpregnant 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 after last infusion and at delivery. Geometric mean ratios (GMR) (90% confidence intervals [CI]) of PK parameters between pregnant and nonpregnant women were calculated.Results Fifty-three participants initiated remdesivir (25 pregnant; median gestational age, 27.6 weeks; interquartile range, 24.9-31.0 weeks). Plasma exposures of remdesivir, its 2 major metabolites (GS-704277 and GS-441524), and the free remdesivir fraction were similar between pregnant and nonpregnant 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 nonpregnant versus pregnant participants. Three adverse events in nonpregnant participants were related to treatment (1 grade 3; 2 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 nonpregnant 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.Clinical Trials Registration NCT04582266. The plasma PK of remdesivir and its major metabolites were comparable between hospitalized pregnant and nonpregnant women with COVID-19, suggesting no dose adjustments are needed for intravenous remdesivir in pregnancy.

Cases of congenital syphilis are rapidly rising. For pregnant women, penicillin G benzathine is the only endorsed treatment option; however, global shortages of penicillin are restricting supply to critical populations. Ceftriaxone (CTX) is a WHO alternative treatment, with limited data on pharmacokinetics (PK) and optimal dosing in pregnancy. Our objective was to characterize expected CTX PK changes during pregnancy using a physiologic-based population PK (PopPK) model to optimize CTX dosing for syphilis treatment. A PopPK CTX model was developed for simulations from existing literature (Pollack 1982, Garot 2011). These limited CTX PK data in pregnancy were leveraged (Bourget 1993, Poavic 2007) with established PopPK pregnancy models that utilize a large repository of anatomic, physiologic, and biologic parameters that change with gestational age, e.g., plasma volume, GFR (Dallmann 2018). Steady-state CTX exposures were predicted in pregnant and non-pregnant persons with different dosing strategies (1g vs 2g IV/IM; q24h, q48h, vs q72h). With all dosing strategies, concentrations were highly variable with lower CTX concentrations in the 3rd trimester compared to non-pregnant persons. Following a 1g IM q24h regimen, as gestation increased, the CTX trough decreased by 58% to 11.7 mcg/mL, 5.9-21.5 (median, IQR) at 40 wks gestation (Figure). The predicted concentration of unbound CTX trough also decreased quicker than in non-pregnancy to < 1% of non-pregnant adult levels due to non-linear binding. Cord blood troughs were predicted to be only 22% of non-pregnant plasma trough levels. Increasing the CTX dose to 2g did not compensate for the changes between pregnant and nonpregnant states nor allow for infrequent dosing. There is a significant decrease in CTX exposure to the mother and fetus in the 3rd trimester regardless of dosing strategy. Currently, effective CTX dosing in vivo is unknown against T. pallidum in pregnancy, however late pregnancy may require different dosing approaches than non-pregnant persons to maintain adequate concentration in the mother and fetus.