Clinical Pharmacology in Drug Development最新文献

The landscape of early-phase drug development is evolving rapidly, driven by both scientific innovation and the increasing adoption of accelerated approval pathways worldwide. The US Food and Drug Administration's (FDA) newly announced Commissioner's National Priority Voucher (CNPV) program marks a potentially transformative moment for drug development in the United States.¹ By offering a radically shortened review timeline—compressing the traditional 10-12 months to just 1-2 months for qualifying applications—the FDA signals both a commitment to innovation and a willingness to rethink its regulatory paradigms to meet urgent national health needs.

As the FDA unveils its new CNPV program, it is worth considering how the traditional playbook for early-phase drug development might be rewritten. For clinical pharmacologists and drug developers, the CNPV program could fundamentally alter the early-phase landscape in several ways.

Although the potential benefits are substantial, several questions remain. The program's initial rollout is limited —a 1-year pilot with a small number of vouchers—so its broader impact will depend on future expansion and the resolution of implementation uncertainties, such as selection criteria and transparency. There is also the perennial concern of ensuring that speed does not come at the expense of scientific rigor or patient safety, a balance the FDA insists will be maintained through multidisciplinary review and ongoing sponsor communication.^{3, 4}

The CNPV program represents a bold step toward modernizing regulatory science and aligning drug development incentives with national health priorities. For early-phase developers, it offers both an opportunity and a challenge: to be ready, nimble, and aligned with the evolving priorities of public health. If successful, the program may serve as a blueprint for future regulatory innovation, catalyzing faster access to transformative therapies while upholding the highest standards of safety and efficacy.

As the pilot unfolds, the clinical pharmacology community will watch closely, eager to see whether this “tumor board” model can deliver on its promise and perhaps redefine what is possible in early-phase drug development.

The author declares no conflicts of interest.

No funding was obtained for this work.

TAK-071 is a novel muscarinic M₁ positive allosteric modulator under investigation for the treatment of cognitive impairment and falls associated with Parkinson disease (PD). This study evaluated population pharmacokinetics of TAK-071 following single (1-160 mg) and multiple (3-15 mg once daily) oral-dose TAK-071 in 112 healthy participants and 53 participants with PD from Phase 1 and Phase 2 studies. A 1-compartment model with a delayed absorption phase adequately described TAK-071 pharmacokinetics. Age, body weight, dose, and formulation were significant covariates. Model simulations indicated that age-adjusted dosing is unnecessary. An exposure-response relationship on cognitive function (attention, executive function, memory, global) was evaluated. Benefits were observed on attention, executive function, and global cognition, and these plateaued between 5 and 7.5 mg once daily, supporting a dose of 7.5 mg for future clinical studies, as 7.5 mg was well tolerated. As patients with PD can have an increased risk of falls, the relationship between cognitive function and risk of falls, as assessed by stride time variability, was explored. Cognition response for the attention domain score showed consistent and sustained improvement in stride time variability compared with when no response was observed, supporting further investigation of TAK-071 in PD for the risk of falls.

This study evaluated the bioequivalence of enoxaparin sodium 100 mg/1 mL solution for injection in a prefilled syringe manufactured by a generic company was compared with the reference product of the same dosage form, in healthy adult volunteers under fasting conditions. The comparison focused on pharmacodynamic (PD) parameters. This open-label, randomized, balanced, 2-treatment, 2-period, single-dose, crossover study involved 60 healthy volunteers. No serious adverse events were reported. Chromogenic assay techniques were used for sample analysis. The linearity range for PD parameters was from 0.100 to 0.800 IU/mL for anti-factor IIa activity, from 0.100 to 0.800 IU/mL for anti-factor Xa activity, and from 750.000 to 10,000.000 pg/mL for tissue factor pathway inhibitor quantification. Statistical analysis was conducted using SAS software Version 9.4. The PD parameters evaluated included maximum observed activity concentration, area under the effect curve from time 0 to time t, median time to maximum concentration, and terminal elimination half-life for anti-factor Xa and anti-factor IIa activity. The 95% confidence intervals for the geometric mean ratio of log-transformed PD parameters between the test and reference products for anti-factor Xa and anti-factor IIa activities were within the range of 80%-125%. It was concluded that the test formulation is bioequivalent to the reference formulation of 100 mg/1 mL solution for injection in a prefilled syringe, under fasting conditions.

Dengue virus infection has become a global health concern, and no dengue-specific treatment is available. Mosnodenvir is a pan-serotypic dengue antiviral in clinical development. In this Phase 1, open-label study (NCT05201937), high- and low-dose weekly, and twice weekly maintenance doses (MDs) of mosnodenvir were evaluated following a twice daily loading dose (LD) over 2 days. The utility of a convenient capillary blood sampling device (TASSO-M20) was also explored. Healthy adults were sequentially assigned to receive: 450 mg twice daily LD, 900 mg once weekly MD; 450 mg twice daily LD, 450 mg twice weekly MD; 150 mg twice daily LD, 300 mg once weekly MD; or 150 mg twice daily LD, 150 mg twice weekly MD. Mosnodenvir exposure rapidly increased with LD and was maintained during the MD phase. In general, mosnodenvir increased in a dose-proportional manner with similar areas under the concentration-time curve between once weekly and twice weekly MD. The mean terminal elimination half-life across treatments was 6.7-8.7 days, supporting less frequent dosing. Safety and tolerability were similar across all treatment regimens. TASSO-M20 was preferred over venipuncture by participants. In summary, mosnodenvir administered weekly or biweekly achieved pharmacokinetic exposures that were found to be safe and well tolerated.

The objective of the current study was to evaluate the rate and extent of absorption of a test formulation (sitagliptin hydrochloride) and a reference formulation (sitagliptin phosphate). An open-label, randomized, single-dose, single-center, 2-sequence, 2-period, and cross-over phase 1 study was implemented to assess the pharmacokinetic bioequivalence of the test and reference formulations containing a single dose of sitagliptin 100 mg in 32 healthy volunteers under fasting conditions. The differences between the test and reference formulations in terms of the area under the curve from dosing to the time of the last measured concentration (AUC_last) and the maximum concentration (C_max) were found to be not significant. The 90% confidence intervals of sitagliptin Ln-transformed AUC_last and C_max were within the pharmacokinetic bioequivalence acceptance range of 80%-125%. The test formulation with sitagliptin hydrochloride was bioequivalent to the reference formulation with sitagliptin phosphate in healthy male volunteers under fasting conditions.

Immunosuppressant tacrolimus is frequently coadministered with other drugs in clinical practice. Ritonavir is a CYP3A irreversible inhibitor that is used in combination with nirmatrelvir for the treatment of COVID-19 in nirmatrelvir/ritonavir. We aimed to apply physiologically based pharmacokinetic (PBPK) modeling to investigate the dose adjustment strategy for tacrolimus during short-term coadministration with ritonavir. PBPK models for tacrolimus and ritonavir were successfully developed based on in vitro and clinical data, and were used to predict drug-drug interaction levels via metabolic enzyme inhibition mechanisms. The recommended dose strategy based on our model simulation is to hold tacrolimus during nirmatrelvir/ritonavir treatment and restart half of the initial dose on day 3 after the 5-day ritonavir course, followed by resuming the full dose on day 5. This administration strategy can maintain trough concentrations of tacrolimus within the therapeutic window during and after ritonavir treatment.

Long-acting cabotegravir is approved for HIV treatment and prevention. To guide management of dosing deviations and interruptions, concentration-time profiles for monthly and every 2 months regimens were simulated using a population pharmacokinetic (PPK) model. Adequate exposure was defined as trough concentration (C_tau) >0.45 µg/mL (observed 5th percentile of first C_tau in pivotal studies) in >95% of subjects and maximum concentration (C_max) <13.1 µg/mL (highest observed median steady-state C_max in previous studies) in >50% of subjects. Simulations showed: (1) median C_max remained ≤6.35 µg/mL after doubled doses; (2) C_tau was suboptimal after half dose at first injection but recovered with a corrective dose; (3) injection delays ≤7 days maintained adequate C_tau, while longer delays caused extended low-exposure periods (≤23 days for 1-month delay, ≤83 days for 3-month delay); (4) reinitiating loading dose after delays >1 month led to higher exposure than continuing injections and may mitigate efficacy loss and resistance risks; and (5) oral bridging (30 mg daily) maintained adequate exposure during delays. Recommended strategies include no action for higher-than-planned doses, corrective dosing for lower-than-planned doses, strict adherence to schedule, reinitiating the loading dose after delays >1 month, and oral bridging. These findings were incorporated into product labeling and can inform next-generation cabotegravir and other long-acting agent development.

Armodafinil, the R-enantiomer of modafinil that promotes wakefulness, was studied regarding its pharmacokinetics and safety in healthy Chinese subjects after multiple-dose oral administration (200 mg daily for 7 days). Twelve subjects participated in this single-center, self-contrast study. The plasma concentrations of armodafinil and its metabolites (R-modafinil acid and modafinil sulfone) were measured by ultra-performance liquid chromatography–tandem mass spectrometry, and drug safety was evaluated during the study. The steady-state accumulation ratio of armodafinil was 1.5, and its metabolites also accumulated with ratios of 1.3 and 7.8, respectively. Although the mean steady-state half-life was similar to that after a single dose, the area under the concentration–time curve, maximum plasma concentration, and clearance of armodafinil changed significantly after multiple dosing. The drug was safe with no serious adverse events, yet fever occurred in 6 subjects, which was not reported before. Modafinil sulfone had significant accumulation, implying the need for further study on its central nervous system–activating properties in Chinese patients.

HT-101, a liver-targeted N-acetylgalactosamine-conjugated ribonucleic acid interference therapeutic, exhibits promising potential for the treatment of chronic hepatitis B virus infection. This randomized, double-blind, placebo-controlled, and single-ascending-dose Phase Ia study included 50 healthy volunteers. Regarding methods, 2 subjects received a single subcutaneous dose of HT-101 at 25 mg, while 48 volunteers were randomized (6:2 active:placebo) in the remaining 6 cohorts to receive a single subcutaneous dose of HT-101 (50-800 mg) or placebo. Afterward, serial blood samples were obtained for pharmacokinetic determination across a 48-hour postdose period. Safety assessments included clinical laboratory measures, vital signs, and 12-lead electrocardiogram before and after dosing. As a result, plasma pharmacokinetics characterized by functional antisense strand revealed a median time to peak plasma concentration of 2.5-6.0 hours, and a short median plasma half-life of 2.50-6.14 hours. It is underlined that peak and total plasma exposure to HT-101 increased in a slightly greater-than-dose-proportional manner following 25-800 mg administered subcutaneously. Moreover, a single dose of HT-101 at 25-800 mg was safe and well tolerated in healthy Chinese volunteers. These data can support further clinical development of HT-101 for hepatitis B virus infection treatment.