The popPK model adequately described canagliflozin PK in healthy volunteers and in patients with T2DM. Because of the small magnitude of statistically significant covariates, they were not considered clinically relevant. However, dosage adjustments are recommended for T2DM patients with renal impairment (eGFR ≥60 mL/min/1.73 m(2): 100 or 300 mg/day; eGFR of 45 to <60 mL/min/1.73 m(2): 100 mg/day).

Understanding persistence of humoral immune responses elicited by vaccination against coronavirus disease 2019 (COVID-19) is critical for informing the duration of protection and appropriate booster timing. We developed a mechanistic model to characterize the time course of humoral immune responses in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-seronegative adults after primary vaccination with the Janssen COVID-19 vaccine, Ad26. COV2.S. The persistence of antibody responses was quantified through mechanistic modeling-based simulations. Two biomarkers of humoral immune responses were examined: SARS-CoV-2 neutralizing antibodies determined by wild-type virus neutralization assay (wtVNA) and spike protein-binding antibodies determined by indirect spike protein enzyme-linked immunosorbent assay (S-ELISA). The persistence of antibody responses was defined as the period of time during which wtVNA and S-ELISA titers remained above the lower limit of quantification. A total of 442 wtVNA and 1,185 S-ELISA titers from 82 and 220 participants, respectively, were analyzed following administration of a single dose of Ad26.COV2.S (5 × 10 10 viral particles). The mechanistic model adequately described the time course of observed wtVNA and S-ELISA serum titers and its associated variability up to 8 months following vaccination. Mechanistic modelbased simulations show that single-dose Ad26.COV2.S elicits durable but waning antibody responses up to 24 months following immunization. Of the estimated model parameters, the production rate of memory B cells was decreased in older adults relative to younger adults, and the antibody production rate mediated by long-lived plasma cells was increased in women relative to men. A steeper waning of antibody responses was predicted in men and in older adults.

BackgroundMonthly injectable CAB LA + RPV LA was noninferior to daily oral 3-drug antiretroviral therapy in HIV-1 virologically suppressed adults. CAB and RPV pharmacokinetics (PK) were assessed during the 48 Week maintenance period of the ATLAS and FLAIR Phase 3 studies.MethodsPatients received oral CAB 30 mg + RPV 25 mg once daily for 4 weeks to assess individual tolerability prior to intramuscular (IM) injections of CAB LA 600 mg + RPV LA 900 mg followed by CAB LA 400 mg + RPV LA 600 mg every 4 weeks. Plasma CAB and RPV concentrations were measured pre-and post-dose at select visits using validated analytical methods.ResultsBaseline demographics for the pooled randomized ATLAS and FLAIR population (n = 591, LA arms) were: median age 38 years, 27% female, 18% African American, median BMI 25 kg/m2 (range: 15 – 51). CAB and RPV plasma concentrations at select visits are summarized in the table. After initial IM doses, mean CAB and RPV troughs were well above their respective in vitro PA-IC90 values (CAB, 0.166 μg/mL; RPV 12 ng/mL). At Week 48, mean CAB troughs were 17x PA-IC90 and between oral CAB 10–30 mg exposures. Similarly, mean RPV troughs were 7x PA-IC90 and remained within the exposure range following oral RPV 25 mg once daily. 80% of RPV steady-state was achieved by Week 48 and 100% for CAB by Week 44. Initial CAB concentrations in females and those with BMI ≥30 kg/m2 were lower due to slower absorption but this difference resolved by Week 48. For RPV, there was no absorption difference by gender or BMI.ConclusionCAB and RPV PK were consistent between studies achieving therapeutic concentrations within the first dosing interval that steadily increased over time through Week 48, for both males and females and irrespective of BMI. CAB LA + RPV LA provided compatible PK profiles following monthly IM dosing in a diverse patient population through 48 weeks. Disclosures All authors: No reported disclosures.

Objectives To characterize the population pharmacokinetics of the rilpivirine long-acting (LA) formulation after intramuscular administration. Methods Rich and sparse rilpivirine plasma concentration data were obtained from seven clinical studies. In total, 18 261 rilpivirine samples were collected from 986 subjects (131 healthy subjects from Phase I studies and 855 people living with HIV from Phase IIb/III studies). Doses ranged from 300 to 1200 mg, as single-dose or multiple-dose regimens (every 4 or 8 weeks). In Phase III studies, an initiation injection of 900 mg followed by continuation injections of 600 mg every 4 weeks was used. Non-linear mixed-effects modelling was performed using NONMEM® software. Results A one-compartment model with linear elimination and two parallel absorption pathways (fast and slow) with sequential zero-first-order processes adequately captured rilpivirine flip-flop pharmacokinetics after intramuscular administration of the LA formulation. The estimated apparent elimination half-life of rilpivirine LA was 200 days. None of the evaluated covariates (age, body weight, BMI, sex, race, health status and needle length) had a clinically relevant impact on rilpivirine pharmacokinetics. Conclusions The population pharmacokinetic model suitably describes the time course and associated variability of rilpivirine plasma concentrations after rilpivirine LA intramuscular administration. The monthly regimen consists of an oral lead-in period (rilpivirine 25 mg tablets once daily for 4 weeks), followed by an initiation injection of 900 mg rilpivirine LA, then 600 mg rilpivirine LA continuation injections monthly. The absence of a clinically relevant effect of covariates on rilpivirine pharmacokinetics suggests that rilpivirine LA dose adjustments for specific subgroups are not warranted.

Receptor occupancy after single dose and at steady state differed for JNJ-37822681 and the robustness of the estimates at steady state will be tested in phase 2 studies. Dose predictions indicated that 10, 20, and 30 mg JNJ-37822681 twice daily could be suitable for these studies.