Pharmacokinetics of intravenous daptomycin in Japanese pediatric patients: Pharmacokinetic comparisons supporting dosing recommendations in Japanese pediatric patients.

INTRODUCTION: The pharmacokinetics (PK) of daptomycin has not been previously characterized in Japanese pediatric patients with complicated skin and soft tissue infections (cSSTI) or bacteremia. An aim of the study includes evaluation of PK of daptomycin in Japanese pediatric patients and an appropriateness of the age-specific, weight-based dosing regimens in Japanese pediatric patients based on PK comparison with Japanese adult patients. METHODS: The phase 2 trial enrolled Japanese pediatric patients (age 1-17 years) with cSSTI (n = 14) or bacteremia (n = 4) caused by gram-positive cocci in order to evaluate safety, efficacy and PK. The Phase 3 trial in Japanese adult patients (SSTI n = 65, septicemia/right-sided infective endocarditis (RIE) n = 7) was referred to for PK comparison between adult and pediatric. Daptomycin concentrations in plasma were analyzed by reverse-phase high-performance liquid chromatography (HPLC). PK parameters were determined using non-compartmental analysis in Japanese pediatric and Japanese adult patients. The exposures in Japanese pediatric patients were graphically compared with those in Japanese adult patients. The relationship between daptomycin exposures and creatine phosphokinase (CPK) elevation was explored visually. RESULTS: Following administration of the age-specific, weight-based dosing regimens, daptomycin exposures were overlapping across age groups in pediatric patients with cSSTI with similar observations based on clearance. The distribution of individual exposure in Japanese pediatric patients was overlapping with that in Japanese adult patients. No apparent relationship between daptomycin exposures and CPK elevation in Japanese pediatric patients was observed. CONCLUSIONS: The results suggested that the age-specific, weight-based dosing regimens are considered to be appropriate in Japanese pediatric patients.

Population pharmacokinetics of tazobactam/ceftolozane in Japanese patients with complicated urinary tract infection and complicated intra-abdominal infection.

Tazobactam/ceftolozane is a combination of a ß-lactamase inhibitor and a cephalosporin antibiotic, with recommended dosage for patients with normal renal function of tazobactam 0.5 g/ceftolozane 1 g administered as a 1-h intravenous infusion every 8 h. The doses in patients with moderate and severe renal impairment are recommended to be reduced by half and 1/4th, respectively. The dose in patients undergoing dialysis is a single loading dose of 750 mg followed after 8 h by a 150 mg maintenance dose. In order to evaluate pharmacokinetics (PK) in Japanese patients, individual Bayes PK parameters were derived using the previously developed population PK models. Furthermore, attainment of PK/pharmacodynamic target in Japanese patients was calculated to confirm the recommended dosage. Based on PK data from 200 Japanese patients in the phase 3 studies, including patients with mild and moderate renal impairment, individual tazobactam/ceftolozane PK parameters were derived. No clinically relevant difference was observed in tazobactam/ceftolozane exposures between Japanese and non-Japanese patients. All Japanese patients achieved a target percent of time that free ceftolozane concentrations are above the minimum inhibitory concentration (MIC) of 30% for MICs of up to 8 µg/mL. Also for tazobactam, all Japanese patients achieved a target percent of time that the free tazobactam concentration exceeds a threshold concentration (1 µg/mL) of 20%. The results suggest that the doses will be efficacious in the Japanese population. The results indicate that the recommended dose in patients with normal renal function or renal impairment is appropriate in Japanese patients.

Population pharmacokinetics of R- and S-carvedilol in Japanese patients with chronic heart failure.

Carvedilol is a beta-adrenoceptor antagonist used for treating chronic heart failure (CHF). Two clinical studies were conducted to evaluate the population pharmacokinetics and pharmacodynamics of R- and S-carvedilol, and associated covariates, in patients with CHF. Fifty-eight patients (male=45, female=13) with New York Heart Association class I-IV CHF were enrolled in two clinical studies. R- and S-carvedilol concentrations were measured using HPLC at steady-state after oral administration of carvedilol at 1.25-20 mg o.d. or b.i.d. The data from both studies were used to estimate the population pharmacokinetic parameters and covariates using the nonlinear mixed effects model program. For 40 patients evaluated in one clinical study, the cytochrome P450 (CYP)2D6 *1, *10, and *5 genotypes were determined using allele-specific primer PCR, and individual patients' oral clearance (CL/F) of both enantiomers were estimated by the empirical Bayes method. A one-compartment model with a first-order absorption rate was established, in which body weight and alpha(1)-acid glycoprotein were significant covariates. Individual CL/F values for carvedilol were significantly lower in Japanese CHF patients with the CYP2D6 *1/*5, *5/*10 and *10/*10 genotypes. Estimation of the population pharmacokinetic parameters and their covariates for each enantiomer in Japanese patients with CHF showed that the CL/F values for R- and S-carvedilol were dependent on body weight, alpha(1)-acid glycoprotein, and CYP2D6 genotype. Prediction of exposure to free plasma carvedilol is important for dosage adjustment of beta-blocker therapy in patients with CHF.

New concept and a theoretical consideration of the mechanism-based pharmacokinetics/ pharmacodynamics (PK/PD) modeling for antimicrobial agents.

Pharmacodynamic (PD) characterization (concentration-dependent, time-dependent, etc.) of antibiotics is determined by aspects of the pharmacodynamic interaction between antibiotics and microorganisms. There are three major aspects of the pharmacodynamic interaction between antibiotics and microorganisms; 1) the minimum drug concentration required for the exhibition of antibacterial activity (MIC: minimum inhibitory concentration, MBC: minimum bactericidal concentration, etc.), 2) the relationship between drug concentration and bactericidal activity and 3) the magnitude of any persistent antibiotic activity (sub-MIC effect, post antibiotic effect, etc.). In the PK/PD approach based on the MIC (static MIC approach), information concerning aspect 1) alone is treated as the quantitative PD parameter (MIC), while information concerning aspects 2) and 3) are not represented as quantified PD parameters in spite of their importance in in vivo pharmacodynamic situation. On the other hand, in the PK/PD approach based on the time-kill profile (dynamic PK/PD approach), information concerning aspects 1) - 3) can all be represented as quantitative dynamic PD parameters (epsilon; the maximum kill rate constant, gamma; the Hill coefficient and EC50; the antibiotic concentration at which 50% of the maximum effect is obtained) together with the growth rates of the organisms (lambda). We thought that the PD characterization of antibiotics should be determined by integrating the dynamic PD parameters and the growth rates, so we developed a new concept integrating these parameters so that a good approximation of the time course of in vivo antibacterial activity exhibited by a antibiotic might be predicted from these parameters and the pharmacokinetics of the drug. To achieve this, we analyzed the time-kill profiles of a wide range of antibiotics against various microorganisms and obtained the dynamic PD parameters and the growth rates for the various combinations of antibiotics and microorganisms. Then we analyzed the causal relationship between the PD characteristics of the antibiotics and the dynamic PD parameters and the growth rates. As a result, we derived the following criteria for predicting the PD characteristics of antibiotics. (i) if the epsilon/lambda is greater than about 10 and gamma is less than one, the pharmacodynamics should be concentration-dependent (ii) if the epsilon/lambda is within the range 1-2 and gamma is about 5 or more, the pharmacodynamics should be time-dependent (iii) if the epsilon/lambda is within the range 1-4 and gamma is in the range 1-12, the pharmacodynamics should be time-dependent or both time- and concentration-dependent. The PD characterization of antibiotics against various strains of different microorganisms can be predicted relatively easily and quickly by utilizing these criteria. These findings make it possible to determine the kinds of causative pathogens to which the antibiotics should be applicable in the clinical sites. Furthermore, it is expected that effective strategies for development and establishing the optimum dosage regimen of novel antibiotics could be worked out more scientifically and efficiently than ever on the basis of the PK/PD parameters corresponding to the predicted PD characters.

Pharmacokinetic and bioequivalence evaluation of single-tablet and separate-tablet regimens for once-daily cobicistat-boosted elvitegravir in healthy Japanese male subjects: A randomized, two-way crossover study.

This randomized, two-way crossover study evaluated the bioavailability of elvitegravir administered as the new individual tablet containing 150 mg and a cobicistat 150 mg tablet, concomitantly with a fixed-dose combination tablet containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (EVG + COBI + FTC/TDF), in comparison with a single-tablet regimen containing the same dose of each component (EVG/COBI/FTC/TDF). Twenty-four healthy Japanese male subjects received the two different elvitegravir treatments, the separate-tablet or single-tablet regimen, once-daily for 10 days in each. The pharmacokinetic parameters (Cmax , AUCtau , and Ctau ) of elvitegravir were investigated at Day 10 after each treatment, together with safety and tolerability. Relative to EVG/COBI/FTC/TDF, the geometric least-squares mean ratios (GMR) and 90% confidence intervals (CIs) for elvitegravir Cmax and AUCtau were within the boundary of 0.8-1.25, while the upper limit of the 90% CI of GMR for Ctau was narrowly below the lack of bioequivalence boundary (0.79). No deaths, serious AEs, or drug-related AEs occurred. In conclusion, Cmax and AUCtau of elvitegravir met the strict definition of bioequivalence, indicating that the two regimens were essentially bioequivalent. Treatment with both regimens for 10 days appeared to be safe and well tolerated.

Effects of a protein-rich drink or a standard meal on the pharmacokinetics of elvitegravir, cobicistat, emtricitabine and tenofovir in healthy Japanese male subjects: a randomized, three-way crossover study.

This study investigated the effects of ingested food types on the pharmacokinetics of elvitegravir, cobicistat, emtricitabine, and tenofovir as a single-tablet regimen (STR) in Japanese HIV-negative healthy subjects. In this open-label, randomized, three-way crossover study, the pharmacokinetic profiles of elvitegravir, cobicistat, emtricitabine, and tenofovir were evaluated when administered with a standard breakfast, under fasting conditions, or with a nutritional protein-rich drink. All subjects (N = 11) received a single morning dose of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (150/150/200/300 mg). Administration under fasting conditions resulted in decreases in the mean AUCinf of elvitegravir and tenofovir by 50% and 28%, respectively, relative to administration with a standard breakfast, whereas the bioavailabilities of elvitegravir and tenofovir were comparable when administered with a standard breakfast or a nutritional protein-rich drink. Under fasting conditions, it appears that the bioavailabilities of elvitegravir and tenofovir were not equivalent to those when they were administered with either type of food, although they were bioequivalent to each other under fed conditions. Cobicistat and emtricitabine were bioequivalent under all conditions. These findings suggest that elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate should be administered with food, and that the bioavailability of elvitegravir and tenofovir is not affected by the type of meal ingested.

Determinants of the over-anticoagulation response during warfarin initiation therapy in Asian patients based on population pharmacokinetic-pharmacodynamic analyses.

UNLABELLED: To clarify pharmacokinetic-pharmacodynamic (PK-PD) factors associated with the over-anticoagulation response in Asians during warfarin induction therapy, population PK-PD analyses were conducted in an attempt to predict the time-courses of the plasma S-warfarin concentration, Cp(S), and coagulation and anti-coagulation (INR) responses. In 99 Chinese patients we analyzed the relationships between dose and Cp(S) to estimate the clearance of S-warfarin, CL(S), and that between Cp(S) and the normal prothrombin concentration (NPT) as a coagulation marker for estimation of IC50. We also analyzed the non-linear relationship between NPT inhibition and the increase in INR to derive the non-linear index λ. Population analyses accurately predicted the time-courses of Cp(S), NPT and INR. Multivariate analysis showed that CYP2C9*3 mutation and body surface area were predictors of CL(S), that VKORC1 and CYP4F2 polymorphisms were predictors of IC50, and that baseline NPT was a predictor of λ. CL(S) and λ were significantly lower in patients with INR≥4 than in those with INR<4 (190 mL/h vs 265 mL/h, P<0.01 and 3.2 vs 3.7, P<0.01, respectively). Finally, logistic regression analysis revealed that CL(S), ALT and hypertension contributed significantly to INR≥4. All these results indicate that factors associated with the reduced metabolic activity of warfarin represented by CL(S), might be critical determinants of the over-anticoagulation response during warfarin initiation in Asians. TRIAL REGISTRATION: ClinicalTrials.gov NCT02065388.

Inter-individual differences in baseline coagulation activities and their implications for international normalized ratio control during warfarin initiation therapy.

BACKGROUND AND OBJECTIVE: Genetic polymorphisms of cytochrome P450 (CYP) 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) and patient demographic characteristics are responsible for inter-individual differences in warfarin maintenance dosage requirements. At present, however, the factors associated with over-anticoagulation responses, especially before achieving the maintenance phase, have not been completely clarified. In this study, we investigated the effects of baseline coagulation activity assessed in terms of the level of fully carboxylated plasma normal prothrombin (NPT) on international normalized ratio (INR) control during the induction phase of warfarin therapy. Our objectives were to (1) identify factors associated with inter-patient variability in baseline NPT (NPT(0)); (2) estimate the therapeutic NPT (NPT(tx)) levels that can achieve an INR of 2-3; and (3) investigate the influence of NPT(0) on the INR response to warfarin by employing modelling and simulation techniques. METHODS: We measured NPT before (NPT(0)) and during the introduction of warfarin therapy for up to 3 months and analysed functional single nucleotide polymorphisms (SNPs) of VKORC1 and CYP4F2 in 179 Chinese patients. The patients were classified into tertile groups according to NPT(0) values (i.e. high, intermediate and low groups), and in each group the NPT(tx) achieving therapeutic INR, the absolute reduction of NPT from NPT(0) to NPT(tx), and the percentage inhibition of NPT(0) [{(NPT(0) - NPT(tx))/NPT(0)} × 100] were obtained. The nonlinear relationship between NPT and INR was modelled on the basis of the INR value before warfarin treatment (INR(0)) added by the nonlinear increase in INR after warfarin initiation, which was predicted using the percentage inhibition of NPT(0) and a nonlinear coefficient (λ). The population parameter λ and its inter-individual variability and intra-individual variability in INR in the NPT-INR model were estimated by nonlinear mixed-effect modelling software NONMEM(®). RESULTS: Multivariate analysis identified age and liver disease as covariates of NPT(0), but none of the SNPs had a significant influence. Although the mean absolute NPT reduction necessary to achieve NPT(tx) was dependent on NPT(0) (i.e. the higher the NPT(0), the larger the reduction in NPT), the percentage inhibition was within the narrow range of 67-72 % of NPT(0), irrespective of NPT(0). However, a significantly higher percentage inhibition (80 % on average) was observed in patients with INR values exceeding 4.0. As the nonlinear coefficient λ in the developed model was dependent on NPT(0) (i.e. the higher the NPT(0), the larger the nonlinear λ value), the simulated nonlinear NPT-INR curves were superimposable in the three respective NPT(0) groups, and the only difference was the starting median NPT(0) level. As a result, a steeper increase in the slope of the nonlinear NPT-INR curve might be expected in patients with a lower NPT(0) after initiation of warfarin. CONCLUSIONS: The present study suggests that INR may be prolonged by warfarin nonlinearly as a function of the percentage inhibition of NPT(0). Furthermore, these results indicate that NPT(0) may contribute to inter-individual variability in the INR response, and that patients with low NPT(0) may have the potential to show a sharp increase in INR during initiation therapy with warfarin.

Association of UGT2B7 and ABCB1 genotypes with morphine-induced adverse drug reactions in Japanese patients with cancer.

PURPOSE: To investigate the effects of genetic polymorphisms on morphine-induced adverse events in cancer patients. METHODS: We examined the relation of morphine-related adverse events to polymorphisms in UDP-glucuronosyltransferase (UGT) 2B7, ATP-binding cassette, sub-family B, number 1 (ABCB1), and µ-opioid receptor 1 genes in 32 Japanese cancer patients receiving oral controlled-release morphine sulfate tablets. RESULTS: The T/T genotype at 1236 or TT/TT diplotype at 2677 and 3435 in ABCB1 was associated with significantly lower frequency of fatigue (grades 1-3) (P = 0.012 or 0.011, Fisher's exact test). The UGT2B7*2 genotype was associated with the frequency of nausea (grades 1-3) (P = 0.023). The frequency of nausea was higher in patients without UGT2B7*2 allele than others. The diplotype at 2677 and 3435 in ABCB1 was associated with the frequency of vomiting (grades 1-3) (P = 0.011). No patient whose diplotype was consisted of no GC allele at 2677 and 3435 suffered from vomiting. CONCLUSION: Our findings suggest that pharmacogenetics can be used to predict the risk of morphine-induced adverse events.