An adaptive design is a clinical trial design that allows for modification of a structured plan in a clinical trial based on data accumulated during pre-planned interim analyses. This flexible approach to clinical trial design improves the success rate of clinical trials while reducing time, cost, and sample size compared to conventional methods. The purpose of this study is to identify the current status of adaptive design and present key considerations for planning an appropriate adaptive design based on specific circumstances. We searched for clinical trials conducted between January 2006 to July 2021 in the Clinical Trials Registry (ClinicalTrials.gov) using keywords specified in the Food and Drug Administration Adaptive Design Clinical Trial Guidelines. In order to analyze the adaptive designs used in selected cases, we classified the results according to the phase of the clinical trial, type of indication, and the specific adaptation method employed. A total of 267 clinical trials were identified on ClinicalTrials.gov. Among them, 236 clinical trials actually applied adaptive designs and were classified according to phase, indication types, and adaptation methods. Adaptive designs were most frequently used in phase 2 clinical trials and oncology research. The most commonly used adaptation method was the adaptive treatment selection design. In the case of coronavirus disease 2019, the most frequently used designs were adaptive platform design and seamless design. Through this study, we expect to provide valuable insights and considerations for the implementation of adaptive design clinical trials in different diseases and stages.

Phage therapy is progressively being recognized as a viable alternative to conventional antibiotic treatments, particularly in the context of multi-drug resistant bacterial challenges. However, the intricacies of the pharmacokinetics and pharmacodynamics (PKPD) pertaining to phages remain inadequately elucidated. A salient characteristic of phage PKPD is the inherent ability of phages to undergo replication. In this review, I proffer mathematical models that delineate the intricate dynamics encompassing the phage, the host organism, and the immune system. Fundamental tenets associated with proliferative and inundation thresholds are explored, and distinctions between active and passive therapies are accentuated. Furthermore, I present models that aim to illuminate the multifaceted interactions amongst diverse phage strains and bacterial subpopulations, each possessing distinct sensitivities to phages. The synergistic relationship between phages and the immune system is critically examined, demonstrating how the host’s immunological function can influence the requisite phage dose for an optimal therapeutic outcome. A profound understanding of the presented modeling methodologies is paramount for researchers in the realms of clinical pharmacology and PKPD modeling interested in phage therapy. Such insights facilitate a more nuanced interpretation of dose-response relationships, enable the selection of potent phages, and aid in the optimization of phage cocktails.

A new sustained-release (SR) pregabalin tablet, YHD1119, was formulated for once-daily dosing. In the current study, we aimed to evaluate the pharmacokinetics of YHD1119 tablets in patients with reduced renal function. Subjects were grouped by creatinine clearance:> 60 mL/min/1.73m 2 (Cohort A) and 30–60 mL/min/1.73m 2 (Cohort B). Eight subjects in Cohort A received a YHD1119 75 mg tablet (Y75T) and a YHD1119 150 mg tablet (Y150T) in each period, and eight subjects in Cohort B received a Y75T. Non-compartment analysis and population pharmacokinetic analysis using a one-compartment model with first-order elimination and first-order absorption with lag time were performed. Sixteen subjects completed the study. The geometric mean ratio (GMR) (90% confidence intervals [CI]) for maximum concentration (C max ), and area under the concentration-time profile from 0 to the last measurable time (AUC last ) after Y75T of Cohort B to those of Y75T of Cohort A were 1.2273 (1.0245–1.4701), and 2.4146 (1.8142–3.2138), respectively. The GMR (90% CI) for C max , and AUC last after Y75T of Cohort B to those of Y150T of Cohort A were 0.6476 (0.5229–0.8021), and 1.1471 (0.8418–1.5632), respectively. Simulated steady-steady pregabalin concentrations after once-daily Y75T dosing in subjects with eGFR 45 mL/min/1.73 m 2 were within the range of steady-state concentrations simulated after once-daily Y150T dosing in subjects with eGFR 90 mL/min/1.73 m 2 . The total pregabalin exposure of Y75T in patients with moderate renal impairment was comparable with that of Y150T in subjects with near-normal renal function.

The venerable drug colchicine has garnered significant recent attention due to its endorsement by the United States Food and Drug Administration as an anti-inflammatory medication for cardiovascular diseases. However, the administration of this drug at its minimal available dose of 0.5 mg has been associated with certain adverse reactions.Once colchicine is administered, the drug disappears from blood in a short time and distributes in the leukocytes for a certain period of time that elicits anti-inflammatory effect.Consequently, an in-depth comprehension of the pharmacokinetics of lower dosages within leukocytes assumes important for its broader application in routine clinical contexts. In this study, we present a comprehensive analysis of the pharmacological disposition of colchicine in the plasma, polymorphonuclear leukocytes, and mononuclear leukocytes among healthy Japanese male subjects, following both single and multiple oral administrations of 0.5 mg and 0.25 mg doses of colchicine. Our investigation reveals that colchicine persists within leukocyte populations even when administered at reduced dosages. The findings herein hold promise for mitigating the adverse effects associated with its use in the treatment of inflammatory cardiovascular disorders.

Endovascular strategies play a vital role in the treatment of peripheral arterial disease (PAD). However, luminal loss or restenosis after endovascular intervention remains a significant challenge. The main underlying mechanisms are negative vascular remodeling and elastic recoil in balloon angioplasty. During stenting, the main reason for this complex is neointimal proliferation. Endothelial cell injury due to endovascular intervention initiates a series of molecular events, such as overexpression of growth factors, cytokine secretion, and adhesion molecules. These induce platelet activation and inflammatory processes, which trigger the proliferation and migration of vascular smooth muscle cells into the intima, resulting in neointimal hyperplasia. During this process, PAD progression is mainly caused by chronic inflammation, in which macrophages play a central role. Of the current strategies, drug release interventions aim to suppress restenosis using antiproliferative drugs, such as sirolimus and paclitaxel, during drug release. These drugs inhibit vascular reendothelialization and reduce late in-stent restenosis. For this reason, immunotherapy can be considered an important alternative. Interventions that polarize macrophages to the M2 subtype are particularly important, as they shape the immune response in an anti-inflammatory direction and contribute to tissue repair. However, there are several challenges to overcome, such as localizing antiproliferative or polarizing agents only to areas of vascular injury. This review discusses, based on the early study observations, immunotherapeutic approaches to prevent restenosis after endovascular intervention for the treatment of PAD.

Wald confidence interval has been used as the conventional method of interval estimation for the parameters in nonlinear models. Because Wald confidence interval is symmetric around the point estimate, it does not reflect the asymmetry of the likelihood profile in nonlinear regression. In contrast, a likelihood interval is estimated directly from the likelihood profile and does reflect the shape of the likelihood profile. However, the lack of software for the estimation of likelihood intervals and visualization of likelihood profiles posed an obstacle to the use of likelihood intervals in nonlinear models. There was a need for software implementation to tackle these tasks. Likelihood interval estimation and likelihood profile plotting for nonlinear models had not been previously implemented in R software. This article describes the implementation of likelihood interval estimation and likelihood profile plotting in the wnl R software package. To demonstrate the usage of implemented functions, an example of fitting a nonlinear pharmacokinetic model to concentration-time data is presented.

Tegoprazan is a novel potassium-competitive acid blocker that treats gastric acid-related diseases. Clarithromycin was widely used as one of various regimens for eradicating Helicobacter pylori. This study compared the pharmacokinetic and safety profile of tegoprazan and clarithromycin between combination therapy and monotherapy to evaluate the potential drug-drug interaction. An open-label, randomized, 6-sequence, 3-period crossover study was conducted in 24 healthy subjects. According to the assigned sequence, the subject was administered the assigned treatment during 5 days in each period. PK parameters of tegoprazan and clarithromycin administered in combination were compared with those of the respective monotherapies. The co-administration of tegoprazan with clarithromycin increased maximum steady-state plasma concentration (C ss,max ) and area under the plasma concentration-time curve in dosing interval at steady-state (AUC ss,tau ) of tegoprazan (1.6-fold in C ss,max and 2.5-fold in AUC ss,tau ) and M1 (2.0-fold in C ss,max , 2.5-fold in AUC ss,tau ) than tegoprazan alone. The C ss,max and AUC sss,tau of 14-hydroxyclarithromycin increased 1.8- and 2.0-fold in co-administration, respectively. The AUC ss.tau of clarithromycin was slightly increased in co-administration, but C ss,max was not changed. Combination of tegoprazan and clarithromycin and those of the respective monotherapies were tolerated in 24 healthy subjects. There may exist drug interaction that lead to reciprocal increase in plasma drug concentrations when tegoprazan and clarithromycin were administrated in combination and no safety concerns were raised. It is suggested that an in-depth analysis of the concentrationresponse relationship is necessary to determine whether these concentration changes warrant clinical action.

This article reviews the Bayesian inference with the Monte Carlo Markov Chain (MCMC) and the Hamiltonian Monte Carlo (HMC) samplers as a competitor of the classical likelihood statistical inference for pharmacometricians. The MCMC and the HMC samplers have greatly contributed to realization of the Bayesian methods with minimal requirement of mathematical theory. They do not require any closed form of the posterior density nor linear approximation of complex nonlinear models in high dimension even with non-conjugate priors. The HMC even weakens the dependency of the chain and improves computational efficiency. Pharmacometrics is one of great beneficiaries since they use complex multivariate multilevel nonlinear mixed effects models based on the restricted maximum likelihood estimation. Comprehension of the Bayesian approach will help pharmacometricians to access the data analysis more conveniently.

This study aimed to compare the pharmacokinetic (PK) and safety profiles of 2 fenofibric acid formulations under fasting and fed conditions. The reference was a 135 mg capsule, while the test was a 110 mg enteric-coated tablet. This randomized, open-label, two-sequence, two-period crossover phase 1 clinical trial was conducted in healthy Korean men. Sixty participants were enrolled in each of the fasting and feeding groups. Blood samples were collected 72 hours after drug administration. PK parameters were calculated using a noncompartmental method with Phoenix WinNonlin ® . A total of 53 and 51 participants from the fasting and feeding groups, respectively, completed the study. The geometric mean ratio and 90% confidence intervals of the maximum concentration (C max ) and area under the concentration-time curve to the last measurable plasma concentration were 0.9195 (0.8795–0.9614) and 0.8630 (0.8472–0.8791) in the fasting study and 1.0926 (1.0102–1.1818) and 0.9998 (0.9675–1.0332) in the fed study, respectively. The time to reach C max of the enteric-coated tablet compared to that of the capsule was extended by 1 and 3 hours under fasting and fed conditions, respectively. In conclusion, enteric-coated tablets have a higher bioavailability than capsules. In addition, the enteric-coated tablet was smaller than the capsule, making it easier for patients to swallow.

Two open-label, randomized, two-period crossover studies were conducted to investigate the pharmacokinetic (PK) properties, safety, and bioequivalence of the test formulation (KD4004), a new fixed-dose combination (FDC) formulation of dapagliflozin and metformin extended release (XR) tablets, relative to the reference formulation (10 mg dapagliflozin/1,000 mg metformin XR FDC tablet) in healthy subjects under fasting (Part A) and fed (Part B) conditions. After giving the dose, serial blood samples were collected for a period of 48 hours. Primary PK parameters (AUC 0-t and C max ) were used to assess bioequivalence between two dapagliflozin/metformin XR (10/1,000 mg) FDC formulations under fed and fasting conditions. Safety and tolerability were also evaluated. Part A and Part B were completed by 32 and 37 subjects, respectively. Bioequivalence of the two FDC formulations of dapagliflozin and metformin XR tablets was established in both the fasted and the fed conditions as the 90% confidence interval of the ratios of adjusted geometric means for AUC 0-t and C max were contained within the predefined range of 0.800–1.250 bioequivalence criteria. Single-dose administration of dapagliflozin and metformin XR was safe and well tolerated as the two FDC formulations. In conclusion, both FDC formulations of dapagliflozin and metformin XR tablets were bioequivalent in fed and fasted subjects. All treatments were well tolerated.