In pregnancy, antiretroviral drug–drug interactions must be interpreted against dynamic changes in gastrointestinal physiology, plasma‐protein binding, renal elimination, hepatic enzyme activity and membrane transporter expression. Interaction studies quantify geometric mean exposure ratios relative to nonpregnant adults, but these measures describe relative pharmacokinetic change rather than whether effective exposure is preserved. For HIV treatment, validated exposure–response targets remain reasonable starting anchors when pregnancy‐specific targets are unavailable. No evidence indicates that gestational immune adaptation alone requires a different intrinsic antiviral target. Pregnancy alters target attainment by altering drug disposition and variability, and it can modify the pharmacokinetics of both the victim antiretroviral and the perpetrator drug. For long‐acting injectable PrEP, protective exposure, dosing interval and pharmacokinetic tail require separate consideration from treatment targets. This review evaluates candidate evidentiary anchors, including protein‐adjusted in vitro inhibitory concentrations, exposure–response relationships, therapeutic drug‐monitoring targets and model‐informed probability of target attainment. Evidence from integrase inhibitors, protease inhibitors, non‐nucleoside reverse transcriptase inhibitors, tenofovir formulations and long‐acting agents demonstrates that similar proportional reductions in exposure can have different clinical implications depending on therapeutic margin, resistance barrier, interaction mechanism, formulation and pharmacologically relevant matrix. A newly proposed six‐domain framework integrates clinical context, active analyte, exposure metric, evidentiary anchor, distributional target attainment and clinical outcomes. Physiologically based and population pharmacokinetic models provide evidence when pregnancy‐specific data are unavailable, but their use should reflect model verification and uncertainty. The central objective is therefore not to define a universal pregnancy threshold but to determine whether pharmacologically effective exposure is maintained in the setting of gestational physiology and c oncomitant medicines.
Aims This study aimed to evaluate the safety, tolerability and pharmacokinetics of a novel oral modified-release psilocybin formulation (REL-P11) in normal-weight and overweight/obese healthy adults and to assess its suitability for controlled, subperceptual exposure, in light of emerging evidence supporting serotonergic modulation in metabolic disorders.Methods Simulation-based modelling compared predicted psilocin exposure with immediate-release formulations. Then, a randomized, double-blind, placebo-controlled, single ascending dose Phase I study was conducted in eight normal-weight and 32 overweight/obese adults. Single oral doses of 0.5, 1.0, 1.5 and 2.0 mg of REL-P11 were administered. Plasma psilocin concentrations were measured using liquid chromatography-mass spectrometry, and pharmacokinetic parameters were derived using non-compartmental analysis.Results Simulations indicated lower peak concentrations and prolonged absorption with the modified-release formulation compared with immediate-release psilocybin. No serious adverse events or adverse events of special interest (AESIs) occurred among REL-P11-treated participants, and no clinically meaningful treatment-related changes were detected in the prespecified psychometric and safety assessments. Psilocin exposure increased proportionally with dose, with low interindividual variability. At the 2-mg dose, pharmacokinetic parameters were broadly comparable between normal-weight and overweight/obese participants, and median time to peak concentration was approximately 2 h.Conclusions Low-dose modified-release psilocybin provides predictable systemic exposure without measurable psychoactive effects across body weight categories. While these properties, together with preclinical evidence, are of potential interest in the context of metabolic regulation, the present findings remain preliminary. Further clinical studies are warranted to determine whether the favourable pharmacokinetic profile observed with controlled subperceptual psilocybin dosing translates into clinically relevant pharmacological and therapeutic effects in metabolic and liver-related disorders.
Aims MT200605 is a novel small-molecule TrkB agonist designed to mimic BDNF for neuroprotection. This first-in-human phase I trial evaluated its safety, tolerability and pharmacokinetics (PK) in healthy volunteers, alongside preclinical data. Methods Preclinical efficacy was assessed in tMCAO rats; PK in healthy rats. The phase I trial was a single-centre, randomized, double-blind, placebo-controlled study comprising single ascending dose (SAD; 0.15-1.2 mg/kg) and multiple ascending dose (MAD; 0.3-1.2 mg/kg/day q12h for 7 days) phases in healthy volunteers. Results In rats, MT200605 at >= 1.35 mg/kg improved day 8 survival (peak survival: 79.2%), reduced infarct volume by 59.7% and improved neurological scores, with quantifiable brain exposure supporting central nervous system penetration. In humans (n = 60), MT200605 was well tolerated, with all drug-related AEs being mild and self-limiting. Free MT200605 demonstrated dose-proportional PK, whereas total MT200605 exposure increased in a slightly more-than-dose-proportional manner during MAD, with no accumulation (R < 2). Steady-state total AUC at 0.6 mg/kg BID (858 h & centerdot;ng/mL) matched the rat efficacious exposure (906 h & centerdot;ng/mL, 5.3% difference). Urinary excretion of total MT200605 was minimal (<4%). Conclusions MT200605 shows promising preclinical neuroprotection and an acceptable safety profile with predictable PK in humans. A twice-daily intravenous regimen of 0.6 mg/kg (1.2 mg/kg/day) is recommended for phase II trials in acute ischaemic stroke patients.
