Gastrin regulates gastric acid secretion and increases when gastric acidity is reduced. Erlotinib, a small-molecule inhibitor used to treat patients with advanced non-small cell lung cancer (NSCLC), has a pH-dependent absorption. We therefore investigated whether elevated gastrin levels, for example, due to proton pump inhibitor (PPI) use or achlorhydria, are associated with reduced erlotinib absorption. Data of patients treated with erlotinib for NSCLC that were included in two previously conducted pharmacokinetic studies were used for this pharmacological proof-of-principle analysis. In these studies, patients were randomized to PPI use or not. Gastrin levels were quantified in samples drawn just before intake of erlotinib and used to study correlations with erlotinib concentrations. The pharmacokinetic endpoints area under the curve (AUC), trough concentration, and maximum concentration (Cmax) were correlated to gastrin concentrations and compared in patients with and without hypergastrinemia (gastrin ≥ 150 pg/mL). A total of 52 patients on erlotinib were included. Gastrin showed a significant inverse correlation with erlotinib AUC0–12h (r = −0.277; p = 0.047) and Cmax (r = −0.423; p = 0.002). In 11 patients with hypergastrinemia (gastrin ≥ 150 pg/mL), median erlotinib Cmax was > 30
Despite extensive research on the pharmacodynamics of follitropin alfa, a comprehensive synthesis of its pharmacokinetic variability is lacking. Understanding the interindividual and intraindividual variability in the pharmacokinetics of follitropin alfa may help inform dosing strategies by reducing variability in systemic exposure. This systematic review aimed to characterise the variability in the pharmacokinetics of follitropin alfa. Embase, PubMed, Scopus and citation mining of included articles were searched from database inception to 10 November 2025. Studies performed in humans, published in English which reported the pharmacokinetics, route of administration and dosing regimen of follitropin alfa were eligible for inclusion. Fifteen eligible studies were evaluated. The pharmacokinetics of follitropin alfa were described by a two-compartment model following intravenous administration, and a one-compartment model with first-order absorption after intramuscular or subcutaneous administration. Follitropin alfa exhibited dose-proportional pharmacokinetics. Moderate interindividual variability (26–42
HHT120 is a novel orally administrable direct thrombin inhibitor. In this study, the pharmacokinetic (PK) profiles of HHT120 and its active metabolite Rn-001 were investigated in a first-in-human study and further analyzed with modeling approaches. Population pharmacokinetic (PopPK) model and pharmacokinetic/pharmacodynamic (PK/PD) model were developed to describe the dose-exposure–response relationship after HHT120 administration. Furthermore, the activated partial thromboplastin time (APTT) under different dosing regimens was performed to evaluate the anticoagulant effect. In total, 74 healthy participants were involved in the dataset involving single ascending dose (SAD), multiple ascending dose (MAD) as well as food effect (FE) phases, and 918 observations of HHT120 concentration as well as 1697 observations of Rn-001 were collected. A total number of 1314 APTT observations were obtained from 62 subjects excluding FE phase. An Erlang model with 7 transit compartments was utilized in the PopPK model to capture the production of Rn-001, and a three-compartment model was employed to describe the disposition. Covariates were screened on the PK parameters in a stepwise style, and no significant covariate effect was found in the current model. Besides, the relationship of plasma concentration of Rn-001 and APTT was characterized by a direct effect with a mixture of linear and nonlinear models. Simulations showed that HHT120 administered once daily at 100–300 mg or twice daily at 100–200 mg led to an increase of APTT within 2-fold of the upper limit, suggesting good safety profiles of HHT120 in the simulated dose regimens. The PopPK/PD model offers evidence for the efficacy and safety properties of HHT120 and are expected to provide valuable insights for subsequent clinical research and development of HHT120. China Drug Trials Registry ( https://www.chinadrugtrials.org.cn ) identifier no. CTR20221837.
The pharmaceutical industry often adopts a stepwise approach, assuming that drug–drug interaction (DDI) results obtained in healthy volunteers (HVs) are translatable to patients. This strategy typically begins with evaluating DDIs in HVs using probe drugs, followed by assessing interactions with potential concomitant medications, often supported by physiologically based pharmacokinetic modeling. Findings from HV studies are subsequently extrapolated to patient populations to inform drug labeling. However, this approach has limitations: (i) DDI results obtained from HV studies may not always be able be to translate to patients due to disease-related physiological changes; (ii) ethical and cost concerns arise when administering investigational drugs to HVs in clinical setting; and (iii) physiologically based pharmacokinetic modeling may be insufficient in predicting DDIs across diverse clinical scenarios. One way to address these challenges is the nested DDI study, where DDI assessments are perceptively embedded within phase II or III clinical trials. [1]. We reviewed US Food and Drugs Administration approvals over recent decades and found that nested/patient-based DDI evaluations were considered sufficient by Food and Drug Administration to support DDI labeling for 86
Polmacoxib (CG100649; Acelex) is a first-in-class non-steroidal anti-inflammatory drug that combines selective cyclooxygenase-2 (COX-2) inhibition with high-affinity binding to carbonic anhydrase I/II (CA-I/II). Approved for osteoarthritis in South Korea (2015) and India (2023), it exhibits pharmacokinetic (PK) properties distinct from other coxibs. The objective of this review is to review the clinical PK and pharmacokinetic–pharmacodynamic (PK–PD) profile of polmacoxib, compare it with other coxibs, and identify key evidence gaps. PubMed, Embase, Scopus, Web of Science, Google Scholar, and ClinicalTrials.gov were searched through June 2026, supplemented by reference lists and regulatory, patent, and Protein Data Bank records. The clinical PK profile of polmacoxib is dominated by erythrocyte sequestration via high-affinity binding to CA-I/II. After oral dosing, whole-blood concentrations exceed plasma concentrations by approximately 50–78 on average, with individual values approaching 120-fold, and terminal half-lives are approximately 121–203 h in blood and 100–167 h in plasma. A 2-compartment whole-blood model with mixed zero- and first-order absorption best describes the data, with serum iron, white-cell count, and age identified as covariates of clearance. The 2-mg once-daily dose substantially inhibits thromboxane B2 and ex vivo PGE2, with only modest, dose-dependent inhibition of urinary prostacyclin metabolite (PGI-M) that is of comparable magnitude, although less sustained, to celecoxib 200 mg after single dosing; the 2-mg dose is noninferior to celecoxib 200 mg on WOMAC pain endpoints in osteoarthritis. Ketoconazole produces only modest changes in plasma exposure, and PK data in hepatic impairment, renal impairment, older people, and non-Korean populations remain limited. Polmacoxib has a unique PK profile among coxibs, driven by erythrocyte carbonic anhydrase binding, which supports its proposed tissue-selective pharmacology. Further studies in special populations, drug–drug interactions, and post-marketing settings are needed to support broader global use.
