Aims Cabotegravir delivered as a long‐acting intramuscular injection has shown superior efficacy to oral tenofovir‐emtricitabine as pre‐exposure prophylaxis (PrEP) for HIV. Cabotegravir pharmacokinetics (PK), like those of other long‐acting depot preparations, exhibit variability between individuals and between injection occasions. The aim of this study is to describe the population pharmacokinetics of long‐acting cabotegravir (CAB‐LA). Methods Using available PK measurements from 133 participants in the HIV Prevention Trials Network (HPTN) 077 trial, we analysed CAB‐LA PK data using nonlinear mixed‐effects modelling to develop a population PK model. Results A two‐compartment model with first order absorption best described the CAB‐LA PK. The analysis identified between‐occasion variability (BOV, i.e., differences in PK within one individual from one injection to the next) as a significant covariate affecting the absorption rate, with an estimated contribution of BOV to PK variability on the absorption rate (ka) of 38.5%. Sex and body weight were identified as significant covariates influencing the absorption rate and apparent clearance of CAB‐LA after intramuscular injection at various doses and frequencies. Male participants had 67% higher ka than female participants. Serially adding to the model body weight on clearance, sex on ka, and BOV on ka led to a decrease in the objective function value (OFV) of 24.4, 36 and 321.4, respectively. Conclusion The public availability of this model will facilitate and enable a wide variety of future clinically relevant simulations to inform the optimal use of CAB‐LA.

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Aim To investigate the relationship between systemic exposure to hydroxychloroquine (HCQ) and its metabolite desethylhydroxychloroquine (DHCQ) and clinical outcome in severely ill patients treated with a standard oral dose regimen of HCQ during the first wave of COVID‐19 in New York City. Methods We correlated retrospective clinical data with drug exposure prospectively assessed from convenience samples using population pharmacokinetics and Bayesian estimation. Systemic exposure was assessed in 215 patients admitted to ICU or COVID‐ward for whom an interleukin‐6 level was requested and who were still alive 24 hours after the last dose of HCQ. Patients received oral HCQ 600 mg twice daily on day 1 followed by 4 days of 400 mg daily. Results Fifty‐three precent of the patients were intubated at 5.4 ± 6.4 days after admission and 26.5% died at an average of 32.2 ± 19.1 days. QTc at admission was 448 ± 34 ms. Systemic exposure to HCQ and DHCQ demonstrated substantial variability. Cumulative area under the serum concentration–time curve up to infinity for HCQ was 71.4 ± 19.3 h mg/L and for DHCQ 56.5 ± 28.3 h mg/L. Variability in systemic exposure was not clearly explained by renal function, liver function or inflammatory state. In turn, systemic exposure did not correlate with intubation status, survival or QTc prolongation. Conclusion This study in severely ill patients was not able to find any relationship between systemic exposure to HCQ and DHCQ and clinical outcome at a routine dose regimen and adds to the growing body of evidence that oral HCQ does not alter the course of disease in COVID‐19 patients.

Objective: To establish in an exploratory neuroimaging study whether γ-hydroxybutyrate (sodium oxybate [SO]), a sedative, anti-narcoleptic drug with abuse potential, transiently inhibits striatal dopamine release in the human.Methods: Ten healthy participants (30 years; 6M, 4F) and one participant with narcolepsy received a baseline positron emission tomography scan of [C-11] raclopride, a D2/3 dopamine receptor radioligand sensitive to dopamine occupancy, followed approximately one week later by an oral sedative 3g dose of SO and two [C-11]raclopride scans (1 h, 7 h post SO). Plasma SO levels and drowsiness duration were assessed.Results: No significant changes were detected in [C-11]raclopride binding in striatum overall 1 or 7 h after SO, but a small non-significant increase in [C-11] raclopride binding, implying decreased dopamine occupancy, was noted in limbic striatal subdivision at one hour (+6.5%; p uncorrected = 0.045; +13.2%, narcolepsy participant), returning to baseline at 7 h. A positive correlation was observed between drowsiness duration and percent change in [C-11]raclopride binding in limbic striatum (r = 0.73; p = 0.017). Conclusions:We did not find evidence in this sample of human subjects of a robust striatal dopamine change, as was reported in non-human primates. Our preliminary data, requiring extension, suggest that a 3g sedative SO dose might cause slight transient inhibition of dopamine release in limbic striatum.

Background Cabotegravir delivered as a long-acting intramuscular injection has shown superior efficacy to oral tenofovir-emtricitabine as pre-exposure prophylaxis (PrEP) for HIV. Cabotegravir pharmacokinetics (PK), like those of other long-acting depot preparations, exhibit variability between individuals and between injection occasions. Aim To describe the population pharmacokinetics of long-acting cabotegravir (CAB-LA). Methods Using available PK measurements from 133 participants in the HIV Prevention Trials Network (HPTN) 077 trial, we analyzed CAB-LA PK data using nonlinear mixed-effects modeling to develop a population PK model. Results A two-compartment model with first order absorption best described the CAB-LA PK. The analysis identified between-occasional variability (BOV, i.e., differences in PK within one individual from one injection to the next) as a significant covariate affecting the absorption rate. Sex and body weight were identified as significant covariates influencing the absorption rate and apparent clearance of CAB-LA after intramuscular injection at various doses and frequencies. Conclusion The public availability of this model will facilitate and enable a wide variety of future clinically relevant simulations to inform the optimal use of CAB-LA.