Ethics

The IMPAACT 2019 study (ClinicalTrials gov identifier NCT03760458) was designed in accordance with the International Council for Harmonization, Good Clinical Practice guidelines [13], and applicable country-specific requirements and abided by the ethical principles of the Declaration of Helsinki. Informed consent was obtained from all the participants before screening. Institutional review boards and national authorities reviewed and approved the trial protocol, amendments, and informed consent forms.

Study Design and Pharmacokinetic Analysis

IMPAACT 2019 (Fig. 1) was an international Phase I/II, multisite, open-label study investigating the PK, safety, tolerability, and efficacy of ABC/DTG/ 3TC FDC (tablets and DT) in pediatric patients < 12 years of age living with HIV-1. Pediatric participants were enrolled concurrently based on five separate weight bands (≥ 6 to < 10 kg, ≥ 10 to < 14 kg, ≥ 14 to < 20 kg, ≥ 20 to < 25 kg, and ≥ 25 to < 40 kg). Intensive PK sampling was performed in the first 5–7 pediatric participants enrolled in each weight band at the Week 1 (Days 5–10) study visit for dose confirmation [14]. Intensive plasma PK samples were collected up to 24 h after dosing (pre-dose, 1, 2, 3, 4, 6, 8, and 24 h post-dose). Sparse PK samples were collected across all participants at Weeks 1 (in participants not undergoing intensive PK sampling at Week 1) pre-dose and at least 2 h post-dose, and at weeks 4, 12, 24, 36, and 48. Among participants with known Met184Val mutations, additional sparse PK samples were collected at weeks 8, 16, and 20. Dose confirmation for each weight band was based on achieving the pre-defined geometric mean (GM) PK targets [area under the concentration–time curve over 24 h (AUC0–24) and concentration at the end of the 24-h dosing interval (C24) for DTG and AUC0–24 for ABC and 3TC] for each drug along with safety outcomes. The GM C24 target range for DTG was 0.697–2.26 µg/ml, and the target GM AUC0–24 was 37–134 µg*h/ml. This DTG target range was selected based on adult PK data and is similar to ranges used in prior pediatric studies [15]. For ABC, the GM AUC0–24 target range was 6.3–50.4 µg*h/'ml, and the 3TC GM AUC0–24 target range was 6.3–26.5 µg*h/ml. These ABC and 3TC targets were selected based on the lower and upper bound of the 90% CIs for predicted exposures with administration once per day in children with HIV [14].

Fig. 1

IMPAACT 2019 study design

Plasma PK samples were analyzed using validated reverse-phase high-performance liquid chromatography paired with tandem mass spectrometry (MS/MS). The lower limit of quantification (LOQ) in plasma was 5 ng/ml, and the upper limit of quantification (ULOQ) was 10,000 ng/ml for all the three components (DTG, ABC, 3TC). In addition, ABC samples below LOQ (5 ng/ml) were further analyzed using a separate ultra-sensitive method with an LOQ in plasma of 50 pg/ml and a ULOQ of 10,000 pg/ml.

PK Modeling MethodsDescription of Established Pediatric PopPK Models for ABC, DTG, and 3TC

The PopPK analysis was performed using NONMEM software, version 7.3.0 (ICON Development Solutions), and run management was performed using Pirana (version 2.9.7). All post-processing diagnostic plots, simulations, post hoc analysis dataset preparation, calculations of secondary PK parameters, and summary statistics were performed using R (version 3.5.1) with RStudio (version 1.1 463). The established pediatric PopPK models for each single entity (ABC, DTG, and 3TC) were previously developed with pooled rich pediatric data. These existing PopPK models were previously used to support the current dosing of each constituent compound in pediatrics. [15, 16]. A brief description of each of the models is provided in the following sections.

ABC Pediatric PopPK Model

The existing ABC PopPK model was a pooled analysis combining six clinical studies[16]. PopPK parameters from this model are presented in Table 1. Plasma ABC exposure following oral dosing in pediatric participants (n = 169) aged 5 months to 13 years of age (4.6–61.3 kg) was well described by a two-compartment model, with IIV on (CL/F), apparent volume of distribution of the central compartment (V2/F) and apparent peripheral compartment volume of distribution (V3/F), intercompartmental clearance (Q/F), and IOV on CL/F. Weight was a significant covariate on CL/F and V/F. A study-specific relative bioavailability term (F1) was included in the model to describe substantially higher observed exposure in the ARROW Substudy Part 2 compared to other studies despite administration of similar doses/formulations [16].

Table 1 Previously reported ABC pediatric PopPK parameter estimatesDTG Pediatric PopPK Model

The existing DTG model was a pooled analysis combining two clinical studies [15]. PopPK parameters from this model are presented in Table 2. Plasma DTG exposure in pediatric participants (n = 239) aged 2 months to 18 years of age (3.9–91.0 kg) was well described by a one-compartment PK model with first-order absorption and first-order elimination, with interindividual variability (IIV) on apparent clearance (CL/F), apparent volume of distribution (V/F), and absorption rate constant (Ka) [15]. The PopPK model accounts for differences in bioavailability across formulations and the impact of food on DTG exposures. CL/F and V/F were allometrically scaled for body weight, respectively, with exponent estimates of 0.455 and 0.556. Inter-occasion variability (IOV) was added to CL/F and Ka. In addition, an enzyme maturation function was applied to CL/F, where half-maximal maturation was 52 weeks post-menstrual age (12 weeks post-natal age) [17]. No other covariates were identified in the model.

Table 2 Previously reported DTG pediatric PopPK parameter estimates3TC Pediatric PopPK Model

The existing 3TC model was a pooled analysis combining six clinical studies [16]. PopPK parameters from this model are presented in Table 3. The plasma 3TC exposure after oral administration in pediatric participants (n = 209) aged 4 months to 19 years of age (3.1–66.4 kg) was well described by a one-compartment model with first-order absorption and first-order elimination. A lag time (ALAG1) for absorption also was included. IIV and IOV were estimated for CL/F, V/F, and Ka [16]. Weight was a significant covariate on CL/F and V/F. A higher absolute bioavailability (F1) estimate was identified for solid dosage forms (tablet and capsule) than for the oral solution, consistent with the results of a 3TC relative bioavailability study conducted in children [18].

Table 3 Previously reported 3TC pediatric PopPK parameter estimatesExternal Model Validation Approach

An external model validation was applied to evaluate the adequacy of the existing pediatric PopPK models to describe the PK and variability in pediatric participants receiving ABC/DTG/3TC DT and tablet in the IMPAACT 2019 study. A sequential modeling approach was employed. The existing pediatric PopPK models were applied to the PK dataset from the IMPAACT 2019 study without re-estimating PopPK parameters (using the MAXEVAL = 0 option in NONMEM). The predictive performance of these existing pediatric PopPK models was evaluated using standard goodness-of-fit (GOF) plots. Simulation-based diagnostics were also used, including visual predictive checks (VPC) and normalized prediction distribution error (NPDE).

Assessment of Predictive Performance of Existing Models

The previously developed individual pediatric PopPK models were used to compute individual predictions of AUC0–24, maximum observed concentration (Cmax), and C24 for each of the individual components of ABC/DTG/ 3TC FDC (DT and tablet) following a steady-state dose for each participant included in the IMPAACT 2019 PopPK analysis. The individual estimates of all model parameters were obtained from the final models by an empirical Bayes estimation method (post hoc estimates from NONMEM). Individual estimates of AUC0–24, (Cmax), and C24 were obtained by simulating the steady-state concentration-time profiles (concentrations simulated at 0, 1, 2, 3, 4, 6, 8, and 24 h) using post hoc PK parameter estimates for each individual. The PK parameters AUC0–24 (calculated by linear up/log down trapezoidal rule), Cmax, and C24, and their summary statistics were computed and stratified by weight bands (all weights bands ≥ 6 to < 10 kg, ≥ 10 to < 14 kg, ≥ 14 to < 20 kg, ≥ 20 to < 25 kg, ≥ 25 to < 40 kg) using R version 3.2.5. These mode1-based, steady-state, post hoc PK parameters were compared with NCA PK parameters [14] to assess the predictive performance of the previous pediatric PopPK models.

Clinical Trial Simulations

Model simulations were performed to evaluate the appropriateness of ABC/DTG/3TC DT and tablet dosing regimen in the pediatric population. The simulations aimed at confirming the anticipated exposure across a wider range of body weights and age ranges. The DTG, ABC, and 3TC concentrations were predicted at 0, 1, 2, 3, 4, 6, 8, and 24 h following steady-state weight-based once-daily doses of ABC/DTG/3TC DT and tablet. Based on the CDC growth charts, pediatric population distributions corresponding to weight bands were constructed. The simulated clinical trial population consisted of 1000 participants, with 200 participants in each weight band, ensuring even distribution of the weights and ages in the simulation [15]. In total, 1000 replicate trials were simulated of 1000 participants with the once-daily ABC/DTG/3TC dosing regimen, and plasma AUC0–24, Cmax, and C24 were calculated for each of the individual drugs.