The relationship between plasma concentrations and inhibitory effects on gastric acid secretion by proton pump inhibitors (PPIs) omeprazole (OPZ), lansoprazole (LPZ) and pantoprazole (PPZ), was analyzed using a pharmacokinetic/pharmacodynamic (PK/PD) model in humans. The estimated values of apparent reaction rate constant of PPI and H+,K+-ATPase (K) were 1.34 +/- 0.17 (microM(-1) x h(-1)), 0.339 +/- 0.002 and 0.134 +/- 0.006 for OPZ, LPZ and PPZ, respectively. The estimated values of apparent turn-over rate constant of H+,K+-ATPase (k) were 0.0252 +/- 0.0019 (h(-1)), 0.0537 +/- 0.0006 and 0.0151 +/- 0.0002 for OPZ, LPZ and PPZ, respectively. The apparent dissociation constants of the H+,K+-ATPase-PPI complex (k/K x fp) corrected with plasma free fraction (fp) were about 1 nM for OPZ and LPZ and 2.3 nM for PPZ. Therefore, the potency of the inhibitory effect of PPZ on acid secretion may be slightly weaker than that of OPZ or LPZ. The apparent half lives (ln2/k) of the inhibitory effect on acid secretion were 12.9 h for LPZ, < 27.5 h for OPZ, and < 45.9 h for PPZ, the recovery rate of the inhibitory effect of PPZ on acid secretion was slowest among these PPIs. In conclusion, the relationship between plasma concentrations and inhibitory effects of PPIs on gastric acid secretion could be analyzed by the PK/PD model.

Development of novel medical products labeled for pediatric use is limited because it is difficult to obtain the safety and pharmacological effect data for the population at the time of approval. The International Conference on Harmonization has issued guidance E11 'clinical investigation of medical products in the pediatric population' to encourage this development. 1) In general, the dosing recommendations for pediatric patients are based on a milligrams per kilogram body weight. However, some drugs are known to exhibit agedependent pharmacokinetics. 2,3) In cases where the pharmacokinetics are represented as plasma clearance 4) or elimination half-life 5) and the disposition is age-related, direct application of the dosing regimen for adults to children with only consideration of body weight is inadequate. Therefore to assess age-related pharmacokinetics, is important and helpful to optimize the dosage regimen for children.Micafungin sodium, a new injectable anti-fungal drug classified as an echinocandin, [6][7][8][9] was first launched in Japan as Fungard TM for the treatment of deep-seated fungal infections such as Candidiasis and Aspergillosis. It was then also approved as Mycamine TM by the US Food and Drug Administration in March 2005 for the prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation and treatment for esophageal candidiasis.10)The pharmacokinetics of micafungin have been investigated in healthy adults, [11][12][13] adult patients undergoing a bone marrow or peripheral stem cell transplant, 14) febrile neutropenic pediatric patients, 15) volunteers with moderate liver disease and renal dysfunction, 16) and a study of drug-drug interaction with Tacrolimus. 17) In Japan, four phase I studies and one Phase II study in adult patients with fungal infections were conducted. Micafungin appeared to be well tolerated, and showed linear pharmacokinetics over the dose range of 2.5 to 150 mg/d (0.5-4.0 mg/kg in children). That is, the maximum plasma concentration of micafungin increased in proportion to the dose, 20) and the elimination half-life (t 1/2 ) was constant for the doses investigated at 13.5Ϯ3.1 h (meanϮS.D., nϭ95). The metabolites of micafungin, M1 (catechol form) and M2 (methoxy form), have comparable pharmacologically active in the experimental infection model, 18) and were detected in the plasma in the steady state after administration to the patient. However the plasma concentrations of M1 and M2 at the dose of 150 mg were very low compared with that of unchanged drug. 11)Thus, while the pharmacokinetics of micafungin and its metabolites in adults has been sufficiently investigated, the pediatric pharmacokinetics remain unclear. In this article, the pharmacokinetic analyses of micafungin and its metabolites in Japanese pediatric patients with fungal infections are described, and their dose-linear pharmacokinetic and age-related pharmacokinetic properties are clarified. The optimal dosage for pediatric use is also proposed herein. MATERIALS AND MET...

IntroductionAmenamevir (ASP2151) is a nonnucleoside antiherpesvirus compound available for the treatment of varicella–zoster virus infections. In this article we summarize the findings of four phase 1 studies in healthy participants.MethodsFour randomized phase 1 studies investigated the safety and pharmacokinetics of single and multiple doses of amenamevir, including the assessment of age group effect (nonelderly vs elderly), food effect, and the relative bioavailability of two formulations. Amenamevir was administered orally at various doses as a single dose (5–2400 mg) or daily (300 or 600 mg/day) for 7 days.ResultsFollowing single and multiple oral doses, amenamevir demonstrated a less than dose proportional increase in the pharmacokinetic parameters area under the plasma drug concentration versus time curve from time zero to infinity (AUCinf) and C max. After single and multiple oral 300-mg doses of amenamevir, no apparent differences in pharmacokinetics were observed between nonelderly and elderly participants. In contrast, with the amenamevir 600-mg dose both the area under the plasma drug concentration versus time curve from time zero to 24 h and C max were slightly increased and renal clearance was decreased in elderly participants. The pharmacokinetics of amenamevir was affected by food, with AUCinf increased by about 90%. In the bioavailability study, AUCinf and C max were slightly lower following tablet versus capsule administration (decreased by 14 and 12%, respectively), with relative bioavailability of 86%. The different amenamevir doses and formulations were safe and well tolerated; no deaths or serious adverse events were reported.ConclusionAmenamevir had less than dose proportional pharmacokinetic characteristics. Age may have an influence on amenamevir pharmacokinetics; however, the effect was considered minimal. The pharmacokinetics of amenamevir were affected by food, with AUCinf almost doubling when amenamevir was administered with food. The concentration versus time profile of the tablet was slightly lower than that of the capsule; the relative bioavailability of the tablet versus the capsule was 86%. Amenamevir was safe and well tolerated in the dose range investigated.FundingAstellas Pharma.Trial registrationClinicalTrials.gov identifiers NCT02852876 (15L-CL-002) and NCT02796118 (15L-CL-003).Electronic supplementary materialThe online version of this article (10.1007/s12325-017-0642-4) contains supplementary material, which is available to authorized users.

The object of this analysis was to develop a population pharmacokinetic model of micafungin, a new anti-fungal agent of the echinocandin class, to optimize dosing in Japanese patients with fungal infections. Population pharmacokinetics parameters were determined using NONMEM based on pharmacokinetic data from 198 subjects in seven clinical studies, comprising four phase I, two phase II and one pediatric phase III study. The healthy subjects received intravenous infusion of 2.5-150 mg micafungin. Adult and pediatric patients, age range of 8 month to 15 yeras old, were received 25-150 mg and 1-6 mg/kg daily, respectively. A total of 1825 micafungin plasma samples were available for this analysis. Two-compartment pharmacokinetic model was adopted. The clearance of micafungin was influenced by body weight in children and platelet counts (PLT). However the PLT accounted for less than 20% of the variation of micafungin clearance in Japanese subjects. In conclusions, body weight is the primary covariate factor in pediatric patients. The dose adjustment by body weight would be required only pediatric patients for the micafungin therapy in Japanese patients with fungal infection.

Background and Objective This study measured and compared the exposure and safety of peficitinib (ASP015K), a novel oral Janus kinase inhibitor, in subjects with normal and impaired renal function after a single oral, clinically relevant peficitinib dose. Methods This was an open-label, parallel-group study conducted at two centres in Japan. Subjects with normal and mildly, moderately, or severely impaired renal function received a single oral dose of peficitinib (one 150 mg tablet) under fasting conditions in a hospital setting. Blood samples were collected prior to administration and up to 72 h post-dose for pharmacokinetic assessment. Safety was assessed up to 7 days post-dose. Results Peficitinib plasma concentration-time profiles were similar between those with normal and impaired renal function. In subjects with impaired renal function, area under the plasma concentration-time curve and maximum concentration were 0.8-to 1.1-fold those in subjects with no impairment. Two subjects (one in the normal group and one in the mildly impaired group) each experienced a treatment-emergent adverse event (TEAE). There were no serious TEAEs, deaths or TEAEs leading to treatment withdrawal. Conclusions Peficitinib exposure and TEAEs were similar in subjects with and without renal impairment after a single oral 150 mg dose. Based on these findings, it is not expected that peficitinib dose adjustment will be required in clinical practice, according to the degree of renal impairment. ClinicalTrials.gov identifier NCT02603497.