Clinical Pharmacology & Therapeutics最新文献

Cedirogant is an inverse agonist of retinoic acid-related orphan receptor gamma thymus developed for the treatment of chronic plaque psoriasis. Cedirogant induces cytochrome P450 (CYP) 3A4 while inhibiting P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, and OATP1B3 in vitro. Static drug–drug interactions (DDIs) predictions suggested possible clinical induction of CYP3A4, and inhibition of P-gp, BCRP, and OATP1B1, leading to challenges in interpreting DDI studies between cedirogant and substrates of CYP3A, P-gp, BCRP, and OATP1B1/3. Here the effects of cedirogant on the pharmacokinetics of two statin drugs were investigated in healthy participants. Coproporphyrin-I (CP-I), a selective endogenous OATP1B biomarker, was used to assess the impact of cedirogant on OATP1B. Cedirogant (375 mg once daily) increased rosuvastatin maximum plasma concentration (C_max) and area under the plasma concentration curve (AUC_tau) by 141% and 55%, respectively when co-administered, whereas atorvastatin C_max increased by 40% with no effect on its AUC_tau compared with administration of rosuvastatin/atorvastatin alone. Cedirogant did not increase CP-I exposures, indicating no clinical OATP1B inhibition. The increased rosuvastatin exposure and minimal change in atorvastatin exposure with co-administration of cedirogant is attributed to BCRP inhibition and interplay between P-gp/BCRP inhibition and CYP3A induction, respectively. Correlation analysis with data from two investigational drugs (glecaprevir and flubentylosin) demonstrated that OATP1B1 R-value of > 1.5 and [C_max,u]/[OATP1B1 IC₅₀] of > 0.1 are associated with > 1.25-fold increase in CP-I C_max ratio. This demonstrates the utility of CP-I in disentangling mechanisms underlying a complex DDI involving multiple transporters and enzymes and proposes refined criteria for static OATP1B inhibition predictions.

Precision dosing can improve drug therapy in complex, critically ill, and chronically ill patient populations who exhibit vast interindividual variabilities in exposures and responses. This perspective outlines five major challenges in precision dosing and highlights their recent progress: (1) application in drug development, (2) improved clinical trials, (3) usefulness of response biomarkers, (4) confidence in model-informed precision dosing, and (5) receptiveness in clinical practice. Many outstanding opportunities in precision dosing remain within regulatory frameworks, data integration and protection, ethics, and reimbursement strategies.

Precision dosing is a foundational pillar of personalized medicine. The term has been applied to different dosing strategies aimed at improving outcomes and safety in complex patients displaying substantial interindividual variability in drug exposure and response. Depending on their degree of individualization, various “precision dosing methods” result in dosing recommendations for patient subgroups based on specific indications, genotypes, or patient characteristics like renal function, and/or in more individualized dosing based on measurements obtained during drug treatment, for example, drug concentrations from therapeutic drug monitoring (TDM). In complex situations in which target effect measurement and data interpretation are not straightforward, multiple pieces rather than a single pieces of information are ideally combined for precision dosing, requiring sophisticated predictive models.

Over the past 5–10 years, precision dosing activities, ranging from dried blood spot analyses of plasma drug concentrations to novel models and educational initiatives fostering better collaboration, have surged, with the goals of benefiting patients, aiding prescribers, saving money, and supporting the development of difficult-to-use drugs. This perspective describes recent advances that address five major challenges of precision dosing (Figure 1), followed by a summary of other challenges with slow progress.

There are strong economic and logistical reasons to limit the number of test doses studied in clinical development. Despite these challenges, precision dosing may be invaluable in tackling complex drug development scenarios, such as for (1) drugs with narrow therapeutic windows, (2) drugs that can lead to severe adverse effects at otherwise typical doses, (3) drugs used for conditions like cancer that carry serious consequences if undertreated, (4) drugs for treating rare, severe, and progressive diseases, and (5) drugs requiring invasive administration routes, for example, intravitreal or intrathecal.¹

Regulatory support is variable, but a successful example of pharma-regulatory collaboration supporting precision dosing is MyPKFit®, a clinical decision support (CDS) tool approved alongside recombinant factor VIII that personalizes dosing in hemophilia A

To compensate for drug response variability, drug metabolism phenotypes are determined based on the results of genetic testing, and if necessary, drug dosages are adjusted. In some cases, discrepancies between predicted and observed phenotypes (phenoconversion) may occur due to drug–drug interactions caused by concomitant medications. We conducted a prospective, exploratory study to evaluate the risk of CYP2C19 phenoconversion in genotyped healthy volunteers exposed to CYP2C19 inhibitors. Three groups of volunteers were enrolled: CYP2C19 g-RM, g-NM, and g-IM (g- for genetically predicted). All volunteers received as CYP2C19 phenotyping substrate 10 mg omeprazole (OME) alone at the control session and in co-administration with CYP2C19 inhibitors: voriconazole 400 mg and fluvoxamine 50 mg in second and third study sessions, respectively. Phenoconversion occurred in over 80% of healthy volunteers, with variations among genotypic groups, revealing distinct proportions in response to fluvoxamine and voriconazole. Statistically significant differences were observed in mean metabolic ratios between CYP2C19 intermediate metabolizers (g-IMs) with *1/*2 and *2/*17 genotypes, with the *2/*17 group exhibiting lower ratios, and distinctions were noted between genotypic groups, emphasizing the impact of genetic variations on drug metabolism. When reclassified according to CYP2C19 baseline-measured phenotype into p-RM, p-NM, and p-IM (p- for measured phenotype), we observed 100% phenoconversion of p-RMs and a significant phenotype switch in p-NMs, p-IMs, and p-PMs after fluvoxamine and voriconazole, and complete phenoconversion of p-IMs to p-PMs on both inhibitors, emphasizing the impact of genetic variations on the vulnerability to CYP2C19 phenoconversion and the importance of considering both genotyping and phenotyping in predicting drug response.

Optimized dosages provide a secure foundation for the development of well-tolerated and effective oncology drugs. Project Optimus, an initiative within the Oncology Center of Excellence, strives to reform the dosage optimization and dosage selection paradigm in oncology. This initiative stems from the availability of targeted drugs and from the demand for more tolerable dosages from patients, caregivers, and advocates. Reforming dosage optimization for oncology drugs requires a paradigm shift from the one employed for cytotoxic chemotherapy to one that understands and considers the unique attributes of targeted therapy, immunotherapy, and cellular therapy. Limited characterization of dosage during drug development may result in (1) patients not staying on a therapy long-term due to poor tolerability, (2) failure to establish positive benefit–risk in clinical trials for regulatory approval (3) withdrawal of drugs from the market (4) removal of indications of drugs from the market. Timely access to drugs is important for all patients with cancer, so it is vital to iteratively analyze all nonclinical and clinically relevant data at each stage of development and leverage quantitative approaches, innovative trial designs, and regulatory support to arrive at dosages with favorable benefit–risk. This review highlights the key challenges and opportunities to embracing this new paradigm and realizing the full potential of new oncology therapies.

Targeted covalent inhibitors (TCIs) are an emerging class of anticancer therapeutics. TCIs are designed to selectively engage their targeted proteins via covalent warheads. From the drug development standpoint, the covalent inhibition mechanism is anticipated to elicit the following theoretical benefits: (i) an extended duration of therapeutic action that is determined by the target protein turnover rate and not necessarily by drug half-life, (ii) a lower therapeutic dose owing to greater pharmacological potency, (iii) lower risk of off-target binding and associated adverse events, and (iv) reduced drug–drug interaction (DDI) liability due to high selectivity and low dose. Elucidating the clinical relevance of these expected benefits requires an integrated assessment of pharmacokinetics (PK), efficacy, safety, and DDI data. In this review, we compared the clinical pharmacology attributes of FDA-approved oncology TCIs within the last 10 years against their reversible inhibitor (RI) counterparts. Our findings indicated that (i) PK half-lives of TCIs were typically shorter and (ii) at their respective recommended clinical doses per drug label, the molar unbound steady state areas under the concentration-time curve (AUC_ss) of TCIs were lower than those of RIs, but with longer clinically observed durations of response. However, (iii) there was no conclusive evidence supporting improved clinical safety profiles for TCIs, and (iv) DDI perpetrator profiles appeared to be similar between TCIs and RIs. The overall clinical pharmacology comparison of TCI vs. RI surveyed in this paper suggested that at least two of the four forecasted clinical benefits were achieved by TCIs.

Mifepristone is an anti-progestational drug that is the first component of the standard medical abortion regimen. For women who take mifepristone and then do not take misoprostol, which is the second component of the medical abortion regimen, it is possible that their pregnancy may continue to live birth. Since mifepristone is commonly used for medical abortion up to 9–10 weeks gestation, any adverse or teratogenic effects on the developing embryo/fetus must be considered, given exposure during the critical time of its development and organogenesis. Toxicology and teratology reports have cited studies demonstrating teratogenic effect of mifepristone in some animals. Current clinical guidelines for women exposed to mifepristone in the first trimester of pregnancy state that it is not known to be teratogenic based on limited published evidence from humans. The aim of this narrative systematic review was to investigate embryonic/fetal exposure to mifepristone and any association with congenital or fetal anomalies. This study was conducted by systematic searches of health databases from inception to February 2024. The references of relevant citations were manually searched to retrieve any additional citations not captured in database searching. Congenital anomalies and adverse outcomes were encountered at various doses of mifepristone exposure. A number of the congenital anomalies encountered in this review were explained by circumstances other than exposure to mifepristone. The present systematic review did not find data to support mifepristone being implicated as a teratogen.

The Pharmacogene Variation Consortium (PharmVar) provides nomenclature for the human CYP2A gene locus containing the highly polymorphic CYP2A6 gene. CYP2A6 plays a role in the metabolism of nicotine and various drugs. Thus, genetic variation can substantially contribute to the function of this enzyme and associated efficacy and safety. This GeneFocus provides an overview of the clinical significance of CYP2A6, including its genetic variation and function. We also highlight and discuss caveats in the identification and characterization of allelic variation of this complex pharmacogene, a prerequisite for accurate genotype determination and prediction of phenotype status.

(R,S)-Ketamine (ketamine) is a dissociative anesthetic that also possesses analgesic and antidepressant activity. Undesirable dissociative side effects and misuse potential limit expanded use of ketamine in several mental health disorders despite promising clinical activity and intensifying medical need. (2R,6R)-Hydroxynorketamine (RR-HNK) is a metabolite of ketamine that lacks anesthetic and dissociative activity but maintains antidepressant and analgesic activity in multiple preclinical models. To enable future assessments in selected human indications, we report the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of RR-HNK in a Phase 1 study in healthy volunteers (NCT04711005). A six-level single-ascending dose (SAD) (0.1–4 mg/kg) and a two-level multiple ascending dose (MAD) (1 and 2 mg/kg) study was performed using a 40-minute IV administration emulating the common practice for ketamine administration for depression. Safety assessments showed RR-HNK possessed a minimal adverse event profile and no serious adverse events at all doses examined. Evaluations of dissociation and sedation demonstrated that RR-HNK did not possess anesthetic or dissociative characteristics in the doses examined. RR-HNK PK parameters were measured in both the SAD and MAD studies and exhibited dose-proportional increases in exposure. Quantitative electroencephalography (EEG) measurements collected as a PD parameter based on preclinical findings and ketamine's established effect on gamma-power oscillations demonstrated increases of gamma power in some participants at the lower/mid-range doses examined. Cerebrospinal fluid examination confirmed RR-HNK exposure within the central nervous system (CNS). Collectively, these data demonstrate RR-HNK is well tolerated with an acceptable PK profile and promising PD outcomes to support the progression into Phase 2.

Variability in drug effectiveness and provider prescribing patterns have been reported in different racial and ethnic populations. We sought to evaluate antihypertensive drug effectiveness and prescribing patterns among self-identified Hispanic/Latino (Hispanic), Non-Hispanic Black (Black), and Non-Hispanic White (White) populations that enrolled in the NIH All of Us Research Program, a US longitudinal cohort. We employed a self-controlled case study method using electronic health record and survey data from 17,718 White, Hispanic, and Black participants who were diagnosed with essential hypertension and prescribed at least one of 19 commonly used antihypertensive medications. Effectiveness was determined by calculating the reduction in systolic blood pressure measurements after 28 or more days of drug exposure. Starting systolic blood pressure and effectiveness for each medication were compared for self-reported Black, Hispanic, and White participants using adjusted linear regressions. Black and Hispanic participants were started on antihypertensive medications at significantly higher SBP than White participants in 13 and 7 out of 19 medications, respectively. More Black participants were prescribed multiple antihypertensive medications (58.46%) than White (52.35%) or Hispanic (49.9%) participants. First-line HTN medications differed by race and ethnicity. Following the 2017 American College of Cardiology and the American Heart Association High Blood Pressure Guideline release, around 64% of Black participants were prescribed a recommended first-line antihypertensive drug compared with 76% of White and 82% of Hispanic participants. Effect sizes suggested that most antihypertensive drugs were less effective in Hispanic and Black, compared with White, participants, and statistical significance was reached in 6 out of 19 drugs. These results indicate that Black and Hispanic populations may benefit from earlier intervention and screening and highlight the potential benefits of personalizing first-line medications.

Cannabidiol (CBD), the main non-intoxicating compound in cannabis, has been hypothesized to reduce the adverse effects of Δ⁹-tetrahydrocannabinol (THC), the main psychoactive and analgesic component of cannabis. This clinical trial investigated the hypothesis that CBD counteracts the adverse effects of THC and thereby potentially improves the tolerability of cannabis as an analgesic. A randomized, double-blind, placebo-controlled, five-way cross-over trial was performed in 37 healthy volunteers. On each visit, a double-placebo, THC 9 mg with placebo CBD, or THC 9 mg with 10, 30, or 450 mg CBD was administered orally. Psychoactive and analgesic effects were quantified using standardized test batteries. Pharmacokinetic sampling was performed. Data were analyzed using mixed-effects model. Co-administration of 450 mg CBD did not reduce, but instead significantly increased subjective, psychomotor, cognitive, and autonomous effects of THC (e.g., VAS “Feeling High” by 60.5% (95% CI: 12.7%, 128.5%, P < 0.01)), whereas THC effects with 10 and 30 mg CBD were not significantly different from THC alone. CBD did not significantly enhance THC analgesia at any dose level. Administration of 450 mg CBD significantly increased AUC_last of THC (AUC_last ratio: 2.18, 95% CI: 1.54, 3.08, P < 0.0001) and 11-OH-THC (AUC_last ratio: 6.24, 95% CI: 4.27, 9.12, P < 0.0001) compared with THC alone, and 30 mg CBD significantly increased AUC_last of 11-OH-THC (AUC_last ratio: 1.89, 95% CI: 1.30, 2.77, P = 0.0013), and of THC (AUC_last ratio: 1.44, 95% CI: 1.01, 2.04, P = 0.0446). Present findings do not support the use of CBD to reduce adverse effects of oral THC or enhance THC analgesia.