Clinical Pharmacology & Therapeutics最新文献

A clinical trial was carried out to investigate the pharmacogenetics of single-dose pravastatin and pitavastatin pharmacokinetics in 173 and 164 healthy participants. Additionally, 96 participants were included from previous pharmacogenetic studies with pravastatin. In a genome-wide meta-analysis of pravastatin including all 269 participants, SLCO1B1 c.521T>C (rs4149056) was associated with increased AUC_0-∞ (P = 9.8 × 10^-12). Similarly, SLCO1B1 c.521T>C was genome-wide significantly associated with increased AUC_0-∞ of pitavastatin (P = 9.7 × 10^-15). Candidate gene analyses suggested that participants with increased function SLCO1B1 variants had decreased pravastatin exposure. Furthermore, decreased function CYP2C9 variants may increase pitavastatin and pitavastatin lactone exposure. Compared to participants with normal function SLCO1B1 genotype, the AUC_0-∞ of pravastatin was 140% (90% confidence interval: 86-210%; P = 4.7 × 10^-8) and 37% (20-56%; P = 1.1 × 10^-4) greater in participants with poor and decreased function SLCO1B1 genotype, respectively, while participants with highly increased function SLCO1B1 genotype had a 60% (39-75%; P = 6.0 × 10^-4) lower AUC_0-∞. The AUC_0-∞ of pitavastatin was 153% (100-222%; P = 1.6 × 10^-9) and 35% (8-69%; P = 0.027) greater in participants with poor and decreased function SLCO1B1 genotype, respectively, than in those with normal function SLCO1B1 genotype. Participants with intermediate metabolizer CYP2C9 genotype had 18% (3-34%; P = 0.046) greater AUC_0-∞ of pitavastatin than those with normal metabolizer CYP2C9 genotype. This study demonstrates the important role of SLCO1B1 in pravastatin and pitavastatin pharmacokinetics and suggests that CYP2C9 variants also affect the pharmacokinetics of pitavastatin.

Tailoring pharmacogenomic (PGx) implementation to diverse populations is vital to promoting health equity. We assessed prescriptions for medications with potentially actionable PGx information to identify patient characteristics associated with differential PGx medication exposure. We analyzed the nationally-representative MEPS dataset of adults who reported receiving prescriptions between 2014 and 2021. PGx medications include those the FDA and CPIC designate as having drug-gene associations supported by scientific evidence. With the primary outcome being PGx prescriptions, we performed Poisson regression adjusted for all other relevant covariates. In our final population (N = 119,722, 72% White/20% Black/4% Asian/8% Hispanic), 61% were prescribed a PGx medication, 56% were female, and 97% held health insurance coverage. Adults with private health insurance (65%) or public Medicaid/Medicare coverage (32%) were more likely to have PGx prescriptions than the uninsured (3%). Individuals with cardiovascular conditions [adjusted IRR (aIRR) = 1.45, 95% CI 1.41, 1.48], high cholesterol [aIRR = 1.37, 95% CI 1.35, 1.40], high blood pressure [aIRR = 1.14, 95% CI 1.12, 1.16], and cancer [aIRR = 1.02, 95% CI 1.00, 1.04] were more likely to receive PGx prescriptions. Self-reported Blacks were less likely than Whites to receive PGx medications [aIRR = 0.92, 95% CI 0.90, 0.94], and among those with health conditions, the likelihood of PGx medication exposure for underrepresented groups (Blacks, Hispanics, and Asians) was lower than for Whites. Our study using a comprehensive list of PGx medications in a nationally representative dataset indicates that certain populations are differentially exposed to genomically informed medications. This may suggest that if implementing a pharmacogenomics program based on reactive testing initiated by a prescription, a small underrepresentation of the Black population could be expected because of an underlying prescription disparity. Secondly, if implementing a pharmacogenomics program based on targeted preemptive testing, using clinical indication/comorbidity may be a reasonable way to enrich the population for prescriptions that would benefit from genotype tailoring.

Psychedelics, such as psilocybin and lysergic acid diethylamide (LSD), are being investigated for the treatment of depressive and anxiety disorders, for which concomitant treatment with selective serotonin reuptake inhibitors (SSRIs) is prevalent. The present study investigated the acute response to single doses of LSD (100 μg) after daily administration of paroxetine (10 mg for 7 days, followed by 20 mg for 35 days) or placebo (42 days) using a randomized, double-blind, cross-over design in 23 healthy participants. Paroxetine did not alter pleasant subjective effects of LSD but significantly reduced "bad drug effect," "anxiety," and "nausea." No differences in autonomic effects or QTc interval after LSD administration were found between both conditions. The strong cytochrome P450 2D6 (CYP2D6) inhibitor paroxetine led to higher maximal concentrations and total exposures of LSD (geometric mean ratios of 1.4 and 1.5, respectively) indicating relevant involvement of CYP2D6 in its metabolism. The extent of this inhibition was nominally highest in genetic CYP2D6 normal metabolizers and lowest in poor metabolizers. The present findings suggest that add-on treatment with LSD to an SSRI is well-tolerated. The pharmacokinetic and pharmacodynamic interactions indicate that no dose adjustment of LSD seems necessary in the presence of an SSRI that inhibits CYP2D6. For SSRIs that do not relevantly inhibit CYP2D6, a dose increase of LSD might be appropriate, but due to lacking data and potential other pharmacokinetic interactions with these compounds, no definitive dose recommendation can be made.

Surrogate endpoints, such as progression-free survival (PFS) and objective response rate (ORR), are increasingly used in oncology trials to expedite drug development and decision making. This paper evaluates the effectiveness of these surrogate endpoints by analyzing their correlations with overall survival (OS) across different cancer types, treatments, and therapy lines at both the patient and trial levels using an integrated dataset from Bristol Myers Squibb. At the patient level, correlation between OS and PFS was consistently stronger than those between OS and best overall response (BOR), suggesting that PFS may serve as a more reliable surrogate for OS. Melanoma patients exhibited the highest correlation between OS and BOR, and immune-oncology (IO) therapy patients showed stronger correlations than those treated with chemotherapy. First-line therapy patients demonstrated stronger correlations between BOR, PFS, and OS compared with second-line or third-line patients. At the trial level, the correlation between PFS hazard ratio (HR) and difference in ORR (∆ORR) was stronger than that between other endpoints. Melanoma studies exhibited strong correlations with significant P-values. IO therapy studies exhibited more consistent correlations.

Pregnancy induces significant adaptations in the cardio-autonomic nervous system, with additional cardiac stress in preeclampsia potentially impacting ventricular repolarization. Despite the widespread use of QT-prolonging drugs during pregnancy, the extent of heart rate (HR)-corrected QT (QTc) interval changes during normal pregnancy and preeclampsia remains unclear. This study aimed to quantify changes in QTc interval across different trimesters of normal pregnancy and third-trimester preeclampsia. Eight databases were systematically searched from their inception to January 13, 2025. Any type of study design, except case reports/series, reporting QT interval and HR or RR interval, and/or QTc interval for at least one trimester were included. Those reporting at least two trimesters or one trimester with nonpregnant controls were pooled in meta-analyses using random-effect models to calculate pooled mean differences (MD) across trimesters. Data from 57 studies (6,686 participants) were included with 33 studies (5,153 participants) pooled in meta-analyses. Compared with nonpregnant individuals, QTc intervals increased across trimesters of normal pregnancy and in third-trimester preeclampsia. Meta-analyses revealed significant increases in QTc interval during first (MD = 10.0 msec), second (MD = 20.2 msec), and third trimesters (MD = 23.0 msec) compared with nonpregnant individuals. Furthermore, preeclampsia increased the QTc interval by 21.7 msec during the third trimester compared to normal pregnancy. No publication bias was detected, and the overall quality scores of most studies were fair (n = 23) or poor (n = 33). A significant QTc interval lengthening throughout normal pregnancy was identified, and to a greater extent during preeclampsia. The arrhythmogenicity in third-trimester preeclampsia with a known risk for QTc interval prolongation, especially with using QT-prolonging drugs, warrants further investigation.

Accurately assessing glomerular filtration rate (GFR) from plasma creatinine concentrations is challenging in patients with unstable renal function. This study aimed to refine the understanding of creatinine kinetics for more reliable assessments of GFR and net creatinine tubular secretion (nCTS) via OCT2/MATE in humans. In a clinical study of 14 healthy volunteers, iohexol was administered intravenously as a reference GFR marker, and creatinine was introduced through a meat meal. A joint pharmacometric model was developed using dense plasma and urine sampling. Simulations were used to evaluate the effect of different creatinine volume of distribution (V_d) values on GFR estimation after acute kidney injury (AKI) and to assess the impact of limited sampling strategies on GFR and nCTS estimation. Pharmacokinetic parameters for iohexol and creatinine aligned with reported values, but a lower V_d of 41% of total body weight and a nCTS fraction of 31% relative to overall creatinine clearance were observed. Commonly used equations based on single-point creatinine measurement all overestimated GFR, with the Modification of Diet in Renal Disease (MDRD) equation performing best, followed by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation. Simulations demonstrate the effect of V_d estimate accuracy on detecting AKI from creatinine plasma concentrations only. Following low-dose iohexol administration, a single plasma sample at 5 hours and a urine sample from 0 to 5 hours provided accurate estimates of both GFR and nCTS using the joint model and enabled adequate correction for incomplete urine collection. This approach shows promise for assessing renal transporter activity based on estimated nCTS.

Drug dose appropriateness is one of the most discussed issues in regulatory reviews. We analyzed dose determinations during Food and Drug Administration (FDA) drug reviews to determine whether there were changes between the proposed and approved doses of new molecular entities (NMEs), including cases where postmarketing dose-finding studies were requested, and explored the factors associated with these decisions. Of the 218 eligible NMEs approved between 2018 and 2022, 28 drugs (13%) had modifications to the proposed dose or requested additional postmarketing assessments, 20 of which were to a lower dose ("downward," 9.2%) and five were to a higher dose ("upward," 2.3%). Multinomial logistic regression analysis suggested that products that used the Accelerated Approval program were more likely to undergo downward modification (relative risk ratio (RRR) = 5.73). In addition, the fact that a dose/exposure-response relationship was observed for safety, but not efficacy, was associated with an increased probability of downward modifications (RRR: 4.27). In contrast, the use of pharmacodynamic biomarkers for dose setting and designation of Priority Review was associated with decreased probabilities of downward change (RRR: 0.405 and 0.195, respectively). Infectious disease drugs went through more upward modifications than those in the other therapeutic categories. This study revealed that dose "optimization" occurs during the FDA's review for drug approval and that not only product characteristics but also factors related to the drug review and approval process are associated with the decisions to modify or question the dose, suggesting considerations for the presence of compelling evidence and restrictions in data availabilities.

PBPK models are gaining special interest as a drug development tool to estimate the effect of intrinsic and extrinsic factors on drug pharmacokinetics. The IQ Consortium Clinical Pharmacology Organ Impairment Working Group conducted a survey across IQ Consortium member pharmaceutical companies to understand current practices on how PBPK is used in understanding the effect of hepatic impairment (HI) on drug disposition and its impact on clinical development. Responses from 21 participants indicated that most organizations (~86%) are already using PBPK models for HI assessment. The survey results indicate that PBPK models have been influential in optimizing the design of dedicated HI study with 57% of respondents using PBPK models to inform the design elements of dedicated HI studies, and the majority of these respondents using the PBPK model to support internal decision making regarding the HI study. Additionally, the PBPK model was used by 62% of the respondents to predict drug plasma protein binding. Despite common usage of the PBPK models by drug developers, 14.3% of the respondents discussed their PBPK modeling strategy with regulatory agencies with only two cases where the regulators accepted the PBPK model. In conclusion, although the use of PBPK models to support regulatory decisions regarding drug use in HI is currently limited, its future is promising, and the success of such models needs collaboration between regulators and drug developers to shrink the knowledge gap in the use of PBPK as an impactful tool for drug development in patients with HI.

Less frequent adverse drug reactions are usually discovered after a drug's release to the market, making effective and timely communication of regulatory post-market advisories essential for preventing emerging adverse effects. Time series analysis is a key study design for assessing the impact of post-market safety advisories. However, most previous studies have focused on narrow evaluations, limiting systematic assessment of how different safety advisories affect prescribing practices. This study aimed to investigate changes in prescribing practices following regulatory post-market safety advisories in Korea. Interrupted time series analyses were conducted using nationwide claims data from 2018 to 2021 and hospital datasets covering the period from 2 years before and 3 years after post-market safety advisories. We categorized the selected drugs into two groups: safety warning through letters and real-time safety alarms (contraindications or requiring attention). Twelve post-market safety advisories were analyzed, including four safety warnings and eight safety alarms, which showed an overall relative reduction (safety warning: relative change [95% confidence interval]: -8.06% [-10.23% to -5.84%], safety alarm on contraindication: -92.65% [-95.65% to -87.59%], and safety alarm on requiring attention: -8.04% [-9.98% to -6.05%]). All types of regulatory interventions reduced the prescribing of targeted drugs; however, the magnitude of these effects differed substantially depending on the type of intervention. By identifying and comparing the influence of regulatory post-market safety advisories, we can enhance these measures to better protect patient health. Continuous monitoring and systematic assessment of safety-related regulatory advisories, with ensured reproducibility, are warranted to optimize effectiveness and ensure safe medication practices.