The Journal of Clinical Pharmacology最新文献

Currently, the same weight-based caffeine citrate dosing regimen is applied to all neonates. However, due to differences in growth trajectories by gestational age (GA) and altered caffeine elimination in neonates with renal injury, optimal dosing regimens may differ. In this study, we refined the existing physiologically based pharmacokinetic (PBPK) model for caffeine in preterm neonates (GA 25–32 weeks) using Simcyp to evaluate dosing across varying ages and renal function. Real-world data were used to generate weight-for-age growth curves and create virtual preterm populations. CYP1A2 ontogeny model was updated to better reflect the reduced metabolic activity of caffeine in preterm neonates. A 13.7-fold increase in glomerular filtration rate-adjusted renal clearance was needed to match observed data. Additionally, a higher volume of distribution (0.96 L/kg) was required to account for increased body water. The final model was verified using clinical pharmacokinetic data and used to simulate plasma concentration–time profiles. Our simulations showed that more premature neonates (≤28 weeks GA) may require lower weight-based maintenance dosing (8 mg/kg) compared with those with higher GA (10 mg/kg), and may also require an increase in doses after 4–6 weeks of therapy to maintain therapeutic levels. Neonates with significantly reduced renal function (25% of normal) may need a two- to threefold dose reduction. Future studies should aim to define optimal therapeutic targets, as caffeine use continues to expand.

Tacrolimus is a first-line immunosuppressant used after solid organ transplantation that suffers from extensive intra- and inter-patient variability and a narrow therapeutic window. Its critical role in a fragile population, coupled with the difficulties identifying and maintaining an appropriate dose within a given patient, make it an ideal candidate for population pharmacokinetic (popPK)-guided individualized dosing approaches (i.e., model informed precision dosing, MIPD). We previously published a tacrolimus popPK model in pediatric heart transplant recipients that showed promise in its ability to predict future concentrations within an individual. Using that model, we developed a Bayesian forecasting decision support tool (DST) clinical use to more rapidly attain appropriate tacrolimus dosing in this population. After rigorous in silico testing of the DST's mathematical fidelity to the popPK model, we implemented the DST within a clinical trial (NCT04380311). Fifteen children between 6 months and 17 years of age had their tacrolimus doses guided by the DST to determine the time to stable therapeutic tacrolimus dosing (defined by three consecutive concentrations within the targeted therapeutic range). DST-guided dosing achieved stable tacrolimus dosing ∼3 days faster (6.9 days, P = .03) as compared to a historical cohort (9.8 days). This was despite the poor performance of the DST in two children treated with continuous renal replacement therapy. These results demonstrate the clinical utility and benefit of the described DST, which is the first targeted to the pediatric heart transplant population. Rapid attainment of stable therapeutic tacrolimus dosing has benefits for the patient, clinician, and the healthcare system.

Posdinemab, a humanized immunoglobulin G1/κ monoclonal antibody, binds with high affinity to phosphorylated tau protein which is associated with Alzheimer's disease (AD) pathophysiology. Posdinemab reduced tau seeding in murine models and was well tolerated in Phase-1 clinical studies. This open-label, single-arm, Phase-1 study examined the effects of posdinemab with single intravenous dose (60 mg/kg) in healthy adults from China. The main objectives were to assess posdinemab serum pharmacokinetics (PK, primary), safety and tolerability (secondary), and presence of anti-drug antibodies (ADAs; secondary). Results were compared with Phase-1 European first-in-human (NCT03375697) and Japanese (NCT03689153) studies. Healthy Chinese participants (N = 10), mean age 60.0 (SD 3.80) years and 60% female, received posdinemab. Mean posdinemab serum C_max was 1401 µg/mL, median t_max was 0.08 days, mean AUC_inf was 18162 µg·day/mL, mean CL was 3.36 mL/day/kg, and mean elimination t_1/2 was 17.5 days. Most participants (n = 8; 80%) experienced ≥1 treatment-emergent adverse event (TEAEs), most common (20%) of which were arthralgia and back pain. Four participants (40.0%) were positive for posdinemab ADAs post-dose with peak titers of 1:22.5 (n = 3) and 1:360 (n = 1). Serum posdinemab concentrations in ADA-positive and ADA-negative participants were generally comparable. In conclusion, PK profile of posdinemab in healthy participants from China was in the expected range and comparable to previous Phase-1 studies in Europe and Japan. There were no new safety concerns. These results support further global development of posdinemab in AD.

There is keen interest amongst the general population in preventing aging and age-related infirmities. Sirolimus is approved for preventing organ rejection in kidney transplant patients, has immune-modulating and growth-inhibitory properties, and is one of the therapies currently being used off-label for this purpose. There is a lack of formal guidance, such as a policy statement or position paper, on the appropriate dosing and administration of sirolimus for aging prevention. The American College of Clinical Pharmacology strongly recommends that clinicians prescribing sirolimus weigh the benefits and risks of sirolimus for off-label use in aging prevention, ensuring patients understand that such prescriptions lack any regulatory approval and rigorous supporting evidence. Health care providers are also encouraged to inform patients of the available clinical evidence and ongoing clinical trials in age-related conditions to build a stronger foundation of safety, efficacy, and optimal dosing for sirolimus in aging prevention.

Dapoxetine is a short-acting selective serotonin reuptake inhibitor used to treat premature ejaculation. However, its clinical effectiveness is challenged by substantial inter-individual variability in pharmacokinetics, as both the drug's therapeutic efficacy and the incidence of adverse reactions are highly dependent on its exposure. This study aims to develop a population pharmacokinetic model for dapoxetine, to investigate the sources of the variability, and to identify demographic and pharmacogenetic factors that influence drug exposure. The pharmacokinetic data for this analysis were obtained from a bioequivalence study conducted in 39 healthy Chinese male subjects. As part of this study, all volunteers were genotyped for the CYP3A4*1G, CYP3A5*3, CYP2D6*10, and CYP2D6*41 allelic variants. Population pharmacokinetic modeling was performed in Monolix. The final model was then used to simulate and compare the effect of different covariate levels on dapoxetine exposure. A two-compartment model with first-order absorption and an absorption lag time best described the pharmacokinetics of dapoxetine. The population parameters for apparent clearance (CL/F), apparent intercompartmental clearance (Q/F), apparent central volume of distribution (Vc/F), apparent peripheral volume of distribution (Vp/F), absorption lag time (Tlag), and absorption rate constant (ka) were 37.8 L/h, 17.2 L/h, 65.6 L, 191.7 L, 0.68 h, and 1.29/h, respectively. CYP2D6*10 and CYP2D6*41 alleles were found to be significant covariates on CL/F. The CYP3A4*1G allele influenced Q/F, while body mass index (BMI) was a significant covariate on Vc/F. Our analysis identified CYP2D6*10 and CYP2D6*41 polymorphisms as the significant factors contributing to inter-individual variability and influencing drug exposure.

The development of good-quality sleep is very important in early life. Sleep promotion programs aim to increase preterm infants’ sleep quality because preterm infants in the neonatal intensive care unit (NICU) have poor sleep. Interestingly, the majority of preterm infants are treated with caffeine, a nervous system stimulant. The primary objective of this systematic review was therefore to appraise the current evidence concerning potentially sleep-disruptive effects of caffeine in preterm infants within the first month of life. We performed a search (PROSPERO protocol CRD42022273596) according to PRISMA guidelines in PubMed, Embase, Scopus, and PsycInfo (as well as CENTRAL). We looked for studies involving preterm infants (<37 weeks of gestational age) treated with caffeine in the NICU, with sleep measures acquired within the first month of life. Eight studies met the eligibility criteria. Underlying effect sizes for main outcomes are represented using albatross plots. Among studies reporting on wakefulness (N = 213), 83.33% detected significant disruptions (P < .05). Among studies reporting on sensorimotor functioning (N = 80), 100% detected significant reductions (P < .05). Moreover, significant reductions (P < .05) in sleep states were detected. Available evidence suggests that caffeine exposure in preterm infants may produce alterations in sleep–wake and sensorimotor functioning, and related processes during the first month of life. The overall evidence is mixed, with some studies reporting no effect of caffeine exposure on neonatal sleep. Additional research is needed to understand how caffeine alters the quality of neonatal sleep in preterm infants and whether the effects may differ among infant subgroups. There is a continued need to investigate and support sleep quality in preterm infants during their NICU stay.

On April 26, 2024, FDA approved Rinvoq (upadacitinib, extended-release [ER] tablets) and Rinvoq LQ (1 mg/mL oral solution), a new pediatric immediate-release (IR) formulation, for the treatment of active polyarticular juvenile idiopathic arthritis (pJIA) and active psoriatic arthritis (PsA) in patients 2 years of age and older. The approved dosing regimens include a weight-tiered twice daily (BID) regimen with IR oral solution and a once-daily (QD) regimen with ER tablets. The objective of this article is to summarize the FDA's major review findings and considerations supporting these approvals from a regulatory perspective. This clinical development program included a single study (Study 1) conducted in pediatric subjects aged 2 to less than 18 years with JIA with active polyarthritis to evaluate the pharmacokinetics (PK), safety, and tolerability of multiple doses of upadacitinib. No clinical trials or dedicated PK studies were conducted in pediatric patients with PsA. Efficacy was extrapolated from adults with rheumatoid arthritis (RA) or PsA to pediatric patients with pJIA or PsA, respectively, based on a PK-matching approach considering disease similarity, similar response to treatment, and comparable PK exposure. PK data analysis and simulations showed that the approved upadacitinib pediatric dosing regimen, including a BID regimen with IR oral solution and QD regimen with ER tablet, provide comparable PK exposure (Cmax and AUC) in pediatric subjects with pJIA or PsA as compared to the approved 15 mg ER tablet QD regimen in adults with RA or PsA, respectively, supporting the efficacy extrapolation from adults to pediatric subjects.

Miricorilant is a novel selective glucocorticoid receptor (GR) modulator with mixed agonist/antagonist effects at the GR and modest antagonism at the mineralocorticoid receptor that is being developed for the treatment of metabolic dysfunction-associated steatohepatitis. Its overall pharmacokinetic characteristics were assessed, including its disposition (absorption, distribution, metabolism, and elimination [ADME]) and drug–drug interaction (DDI) potential. In vitro, miricorilant (1) demonstrated >99% plasma protein binding in mice, rats, monkeys, and humans, (2) was a modest inhibitor of CYP3A4, CYP2C8, CYP2C9, UGT1A1, and a strong inhibitor of BCRP, (3) was predominantly metabolized by CYP2C19 (≈94%), and (4) showed no induction potential for CYP1A2 and CYP2B6, but showed a concentration-dependent induction of CYP3A4 (6.5-fold) in 1 out of 3 donors tested. In a tissue distribution study in mice, miricorilant was distributed with high levels of radioactivity present in several tissues, including the liver. In animal and human ADME studies, the majority of total radioactivity was recovered in feces (>78%) versus urine (<5%), suggesting hepatic elimination with minor contribution of renal elimination. In phase 1 clinical studies in healthy subjects, miricorilant showed an approximately dose-proportional increase in systemic exposure in the dose range 100–900 mg with an elimination half-life of ≈20 h. In clinical DDI studies at the total plasma concentrations evaluated, miricorilant was a strong inhibitor of CYP2C8 and a moderate inhibitor of BCRP with no meaningful inhibition of CYP2C9, CYP3A4, or UGT1A1, and a moderately sensitive substrate of CYP2C19. Miricorilant was safe and well-tolerated in the phase 1 studies.

Bemnifosbuvir is a novel oral guanosine nucleotide prodrug candidate for the treatment of chronic hepatitis C virus infection. Potential drug–drug interactions (DDIs) of bemnifosbuvir as a substrate or perpetrator with regard to ATP-binding cassette (ABC) and solute carrier (SLC) transporters were evaluated in vitro and in clinical studies. Bemnifosbuvir was demonstrated in vitro as a substrate and inhibitor of the ABC transporters’ P-glycoprotein (P-gp), as an inhibitor of the breast cancer resistance protein (BCRP), as well as a weak inhibitor of SLC transporters, including organic anion transporting polypeptide 1B1 (OATP1B1). Phase 1 studies in healthy participants were subsequently conducted to assess the clinical significance of transporter-mediated DDI potentials of bemnifosbuvir as a precipitant using digoxin and rosuvastatin as P-gp and BCRP/OATP1B1 index substrates, respectively. A single dose of 0.25 mg digoxin or 10 mg rosuvastatin was administered alone and with 1100 mg bemnifosbuvir, either simultaneously or staggered. Simultaneous administration of a single dose of 1100 mg bemnifosbuvir increased total plasma exposure of both drugs by less than 20%, and transiently increased the peak plasma exposure of digoxin and rosuvastatin by 78% and 40%, respectively. Staggered dosing reduced the magnitude of changes in peak exposure to digoxin and rosuvastatin. No serious adverse events or drug discontinuations were observed. Dose adjustments are therefore unlikely for drugs that are substrates of P-gp or BCRP/OAT1B1 when coadministered with bemnifosbuvir, and staggered dosing may further reduce any DDI risk.