The Journal of Clinical Pharmacology最新文献

Given the significant impacts of interindividual genetic variability on drug safety and pharmacokinetics, integrating pharmacogenetic (PGx) considerations into pharmacokinetic (PK) bioequivalence (BE) study design can improve subject safety and data robustness in generic drug development. While PGx information has been often utilized in new drug development, its use in generic drug development has not been fully considered. To understand the current landscape of its utility in generic drug development, product-specific guidances (PSGs) from the US Food and Drug Administration (FDA) containing PGx information were reviewed, along with study protocols submitted by generic drug applicants under abbreviated new drug applications (ANDAs) or controlled correspondences for the identified reference listed drugs (RLDs). Fifteen PSGs (15 RLDs) recommended PGx information as a consideration factor for subject population selection, particularly for drugs associated with inherited enzyme deficiencies or cytochrome P450 polymorphism. The PGx-based considerations in these PSGs aimed to prevent serious adverse events (60%), optimize PK BE study design (7%), or address both factors (33%). Among the 15 RLDs, 5 had submitted ANDAs or correspondences with PK BE study protocols after their respective PSGs were published. Most of these submissions aligned with the PSG recommendations, incorporating PGx-related exclusion criteria. These findings suggest that while the number of submissions is low, generic drug developers are increasingly integrating PGx considerations in PK BE studies, recognizing its potential to enhance safety and efficiency in generic drug development. Continuing efforts from both regulators and industry are critical to expand its application to other drug candidates.

VRC01 and VRC01LS are a pair of parental and LS-modified anti-HIV IgG1-backboned monoclonal antibodies. In a Phase 1 clinical trial HVTN 116, 79 participants without HIV received intravenously one dose of VRC01 (30 mg/kg, n = 16) or VRC01LS (30 mg/kg, n = 10), four doses of VRC01 (10 mg/kg, n = 23 or 30 mg/kg, n = 23) every 2 months, or three doses of VRC01LS (30 mg/kg, n = 7) every 3 months. Participants were followed for 6 (VRC01) or 12 (VRC01LS) months after the last dose. Using nonlinear mixed-effects models, we conducted the first population pharmacokinetics analysis of VRC01/LS concentrations in serum and rectal tissue, a primary site of HIV transmission. Serum concentration was described as a one-compartment model in equilibrium with one tissue compartment, with first-order elimination in both compartments. The model was parameterized with micro-constants to estimate volumes of distribution for serum and tissue, serum–tissue distribution rates (K12, K21), and elimination rate constants; distribution and elimination half-life estimates were derived from the governing differential equations. To account for rectal biopsy heterogenicity between individuals, three normalization approaches were used: tissue weight adjusted, IgG concentration adjusted, and protein concentration adjusted. All three approaches rendered consistent estimates. Based on protein-concentration-normalized data, VRC01LS (vs VRC01) exhibited ∼10-fold higher concentrations over time in blood and rectal tissues, and faster blood-to-tissue distribution (K12 = 0.61 vs 0.13/day). Median elimination half-life estimates were 20 days for VRC01 and 63 days for VRC01LS in serum and rectal tissues. These data support lower dosage and/or less frequent dosing of LS monoclonal antibodies providing potentially more immediate protection against HIV exposure in the rectum.

Fruquintinib is a highly selective oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, approved by the US Food and Drug Administration and the European Commission for the treatment of previously treated metastatic colorectal cancer (mCRC), regardless of biomarker status. This study used concentration QT interval (C-QTc) modeling, utilizing data from the phase 3 FRESCO-2 study (NCT04322539) in which patients with mCRC received fruquintinib 5 mg, once daily, or matching placebo in a 28-day cycle, to evaluate the potential of fruquintinib to delay cardiac repolarization. The primary objectives were to assess the relationship between change from baseline in the QTc and plasma concentrations of fruquintinib and its metabolite M11, and to predict placebo-corrected change from baseline in the corrected QT interval (ΔΔQTc) associated with clinically relevant fruquintinib or M11 concentrations. The C-QTc analysis was conducted using 1456 time-matched concentration-change from baseline in the population-based corrected QT interval (ΔQTcP) pairs from 205 patients (fruquintinib n = 137; placebo n = 68). The final C-QTc model was a linear mixed-effects model with the effect of M11 concentration on ΔQTcP. This model estimated that the upper bounds of the 90% CI of the mean ΔΔQTcP at steady-state geometric mean (GM) M11 C_max, and twice the GM M11 C_max were 0.0537 and 4.00 ms, respectively. Additional C-QTc analysis, including only fruquintinib concentrations, showed no relationship between ΔQTcP and fruquintinib concentrations. The analysis indicated that fruquintinib administered at the approved clinical dose is not anticipated to cause clinically meaningful QT prolongation.

Plozasiran, a novel small interfering RNA therapeutic targeting the hepatic biosynthesis of apolipoprotein C-III, has successfully completed the pivotal Phase 3 trial for treatment of familial chylomicronemia syndrome. The Phase 3 trials of plozasiran conducted in patients with severe hypertriglyceridemia (SHTG) are currently ongoing. An integrated population pharmacokinetic (PPK) model was developed by combining plozasiran pharmacokinetic (PK) data from healthy volunteers and patients with varying severities of hypertriglyceridemia (HTG) enrolled in five clinical studies. Plozasiran plasma PK were described by dual first-order absorption kinetics following subcutaneous administration, a one-compartment model of systemic distribution, and a dose-linear, time-independent rate of clearance. Evaluation of covariates identified body weight (BW) and body mass index (BMI) as the only independent intrinsic factors to influence plozasiran PK with statistical significance, although without clinical importance. The PPK analysis supports a fixed dosage of plozasiran for all patients regardless of BW, BMI, sex, age, race (including the Asian population), differing severity of HTG, mild to moderate degrees of renal impairment, or a mild degree of hepatic impairment. As plozasiran PK were not differentiated by patient population, a substantially reduced schedule of PK sampling was justified for the ongoing Phase 3 studies to confirm the safety and efficacy of plozasiran in patients with SHTG. Model-based extrapolation of plozasiran concentrations in plasma and liver suggests that the plozasiran dosing regimen of 25 mg every 3 months recommended for adult patients is likely safe and effective in adolescent patients aged 12 to 17 years old.

Secukinumab has been widely applied in adults for the treatment of plaque psoriasis and psoriatic arthritis. However, there remains a knowledge gap in the dosing of secukinumab for pediatric patients with plaque psoriasis. This study aims to investigate the dosing regimen for pediatric patients aged 2 years and older. A physiologically based pharmacokinetic model for secukinumab was developed and validated in adult patients. Based on this model, two additional observation compartments for total interleukin-17A (IL-17A) and skin free IL-17A were incorporated to evaluate the inhibition of secukinumab on its targets. Ultimately, this model was extrapolated to pediatric patients. The model precisely captured the pharmacokinetic profiles and serum total IL-17A levels observed in different studies, encompassing various dosing schedules and formulations. Pediatric patients were stratified by weight, and the model incorporated age-related developmental factors. Using the inhibition of skin free IL-17A during steady-state treatment as a benchmark for a 300 mg adult dose indicates that pediatric patients weighing less than 25 kg require 75 mg, those weighing between 25 and 50 kg require 150 mg, and patients weighing more than 50 kg require 225 mg to achieve similar levels of inhibition. This conclusion provides new ideas for flexible medication use in pediatric patients with psoriasis.

Peptides are oligomers with ≤40 amino acids and are regulated as small molecule drugs. Peptides can exhibit certain clinical pharmacology features characteristic of small molecule drugs and others characteristic of biologics. To inform best practices in clinical pharmacology, we reviewed general characteristics of peptides approved by US Food and Drug Administration before July 2022 and how often clinical pharmacology information, and corresponding recommendations were discussed in drug labeling. For peptides, clinical pharmacology information was available in the labeling related to renal impairment for 57% (30/53), drug–drug interactions for 49% (26/53), immunogenicity for 40% (21/53), hepatic impairment for 38% (20/53), QT interval assessment for 34% (18/53), and mass balance for 17% (9/53). Actionable clinical pharmacology recommendations found in labeling related to each survey topic were catalogued and included dose adjustments and risk mitigation strategies.

QY201 is a dual inhibitor targeting Janus Kinase 1/Tyrosine Kinase 2, developed for the treatment of atopic dermatitis and other autoimmune diseases. The pharmacokinetics (PK), pharmacodynamics (PD), tolerability, and safety of QY201 were assessed in a randomized, double-blind study in healthy subjects. Population PK and PD models were developed to characterize the PK and PD of QY201. QY201 was absorbed and eliminated rapidly, and the exposure was approximately dose-proportional over the 1-40 mg dose range, with no significant accumulation after repeated dosing. A high-fat meal reduced the maximum plasma concentration of QY201 by 40.7% but did not affect the area under the concentration-time curve. The fraction of the QY201 dose eliminated in the urine unchanged was 22%. In the multiple ascending-dose phase, the reduction of hypersensitive C-reactive protein (hsCRP) and absolute neutrophil count (ANC) showed dose-dependent trends within certain doses. The PK of QY201 was best described by a 2-compartment model with first-order absorption and elimination. The hsCRP was best described by an indirect response maximum drug effect (E_max) model. QY201 was generally safe and well tolerated following oral administration, with dose-limiting toxicity of the highest tested dose of 40 mg being well tolerated. The favorable PK, PD, safety, and tolerability results from these studies supported evaluations of QY201 in future clinical trials.

The Spanish Pharmacovigilance System for Medicines for Human Use (SEFV-H) is responsible for recording and evaluating adverse reactions suspected to be due to medicines. The aim of this study was to review all reports of suspected adverse drug reactions (ADRs) in the SEFV-H database derived from the gender-affirming hormone therapy (GAHT). For this purpose, we consulted the Andalusian Centre for Pharmacovigilance (CAFV) and used three search algorithms to select only those reports derived from hormone therapy used by trangender people. A total of 21 reports were obtained, 13 corresponding to masculinizing therapy with testosterone and 8 corresponding to feminizing therapy with estradiol and cyproterone acetate. Most of these reports were of non-serious symptoms. Skin and subcutaneous tissue disorders, neoplasms, and psychiatric, vascular, gastrointestinal, and nervous system disorders were the most common suspected ADRs. The median age was 23.6 years for masculinizing therapy and 27 years for feminizing therapy. These data highlight the need for well-designed studies specifically focused on transgender people undergoing hormone therapy. Such studies are essential to develop evidence-based treatment guidelines tailored to this population and to provide accurate, population-specific information about the potential health risks associated with gender-affirming hormone use.