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.

Pharmacokinetics, Safety, and Tolerability of Letermovir Following Single- and Multiple-Dose Administration in Healthy Japanese Subjects.

Letermovir is a human cytomegalovirus terminase inhibitor for the prophylaxis of cytomegalovirus infection and disease in allogeneic hematopoietic stem cell transplant recipients. The pharmacokinetics, safety, and tolerability of letermovir were assessed in healthy Japanese subjects in 2 phase 1 trials: trial 1-single ascending oral doses (240, 480, and 720 mg) and intravenous (IV) doses (240, 480, and 960 mg), and trial 2-multiple oral doses (240 and 480 mg once daily for 7 days). Following administration of oral single and multiple doses, letermovir was absorbed with a median time to maximum plasma concentration of 2 to 4 hours, and concentrations declined in a biphasic manner with a terminal half-life of ≈10 to 13 hours. The post absorption plasma concentration-time profile of letermovir following oral administration was similar to the profile observed with IV dosing. There was minimal accumulation with multiple-dose administration. Letermovir exposure in healthy Japanese subjects was ≈1.5- to 2.5-fold higher than that observed in non-Japanese subjects. Based on the population pharmacokinetic analysis, weight differences primarily accounted for the higher exposures observed in Asians. Letermovir was generally well tolerated following oral and IV administration to healthy Japanese subjects.

Correlation between pharmacokinetic/pharmacodynamic indices and clinical outcomes in Japanese patients with skin and soft tissue infections treated with daptomycin: analysis of a phase III study.

The relationships between pharmacokinetic (PK)/pharmacodynamic (PD) indices and outcomes were investigated in patients with skin and soft tissue infection (SSTI) who received daptomycin at 4 mg/kg/day. Efficacy was evaluated in 55 patients from whom Staphylococcus aureus was isolated, with success rates of 94.5% and 69.1% for clinical and microbiological responses, respectively. The odds ratio for the relationship between the area under the day 1 concentration-time curve (AUC0-24h) to the MIC and the probability of clinical success was 1.03 (95% confidence interval [CI] 0.73-1.45), and that for the relationship for probability of microbiological success was 0.94 (95% CI 0.81-1.09). In 82 patients in the safety analysis, only 1 met the creatine phosphokinase (CPK) elevation criteria, and this patient's minimum concentration (C(min)) of plasma daptomycin was 5.37 µg/mL. No significant relationship was found between peak CPK and C(min) (Pearson's correlation coefficient -0.0452). In conclusion, no clear correlation between PK/PD indices and the probability of efficacy or safety events was demonstrated when daptomycin was administered in SSTI patients using the clinically recommended dosage of 4 mg/kg/day.

Interaction of serum proteins with CYP isoforms in human liver microsomes: inhibitory effects of human and bovine albumin, alpha-globulins, alpha-1-acid glycoproteins and gamma-globulins on CYP2C19 and CYP2D6.

The effects of serum proteins on the in vitro hydroxylation pathways of mephenytoin (CYP2C19) and debrisoquine (CYP2D6) were studied to enhance the predictability of in vivo drug metabolism from in vitro assays. Both CYP substrates are known to be weakly bound to albumin and the applicability of the free drug hypothesis was further appraised. Since bovine serum albumin (BSA) is used widely in in vitro assays, a comparison between human and bovine proteins was made. Four major serum proteins were studied: albumin, alpha1-acid glycoprotein (AGP), alpha- and gamma-globulins. Human serum albumin (HSA) inhibited both CYP activities about 20% more than BSA. The addition of human alpha-globulins, but not the bovine protein, resulted in marked reduction of 86% and 41% in CYP2C19 and CYP2D6 activities, respectively. This reduction of activity was strikingly greater than the fraction bound (14 and 22%, respectively). The inhibition was of the competitive type and the Ki values of human alpha-globulins on CYP2C19 and CYP2D6 were found to be 0.45% (4.5 mg/ml) and 3.5% (35 mg/ml), respectively. The effect of both human and bovine gamma-globulins on CYP isoforms was negligible. The Ki values of human and bovine AGP for CYP2C19 were 1.84% (420 microM) and 0.93% (210 microM), respectively. For HSA, human alpha-globulins and human and bovine AGP, the strongly decreased CYP activities in vitro cannot be explained by the free drug hypothesis. A direct interaction of these serum proteins with CYP enzymes is postulated. Differential effects of bovine and human serum proteins and CYP specific inhibition were observed.

Sensitive and selective liquid chromatography-electrospray ionization tandem mass spectrometry analysis of hydrochlorothiazide in rat plasma.

A sensitive and selective method for the determination of hydrochlorothiazide (HCTZ) concentrations in rat plasma was developed using high performance liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS). An aliquot of plasma (50 microl) was mixed with the solution of internal standard, hydrofluorothiazide (HFTZ), and extracted with tert-butyl methyl ether. The reconstituted extract was applied to the LC-MS/MS system with a reversed phase C8 column and eluted with distilled water/acetonitrile (85/15, v/v). To enhance negative ionization of HCTZ and HFTZ in the multiple reaction monitor (MRM), the solution consisting of acetonitlile/1% (v/v) ammonia solution (95/5, v/v) was delivered after column separation. This additional technique, so-called the post-column addition, increased sensitivity of HCTZ and HFTZ about 500- and 200-fold, respectively. The calibration curve showed good linearity (r = 0.999) over the range of 4-1000 ng/ml. Acceptable accuracy (100.8-113.1%) and precision (0.28-16.4%) were confirmed in the intra- and the inter-day analyses. It is indicated that this LC-MS/MS method is useful for pharmacokinetic studies of HCTZ in small animals, because it enabled the serial determination of plasma level of HCTZ in rats.

The interaction of human and bovine serum proteins with CYP3A in human liver microsomes: inhibition of testosterone 6beta-hydroxylation by albumin, alpha-globulins, alpha(1)-acid glycoprotein and gamma-globulins.

The effects of human and bovine serum proteins on CYP3A activity, using testosterone as the probe substrate, were investigated in human liver microsomes. Serum albumin, alpha-globulins, and alpha(1)-acid glycoprotein (alpha(1)-AGP) of both species significantly inhibited testosterone 6beta-hydroxylation. When the inhibitory effects of serum proteins were compared with serum protein binding data, human alpha-globulins, with a ratio (relative metabolic activity/unbound fraction) of 0.3, showed higher, and bovine alpha(1)-AGP, with the ratio of 1.4, showed lower inhibitory effects than those expected from protein binding of testosterone. The effects of the other serum proteins were close to those expected from protein binding, according to the free drug hypothesis. The K(i) values obtained from the Dixon plots were 0.32% (w/v, 48 microM) for human serum albumin (HSA), 0.48% for human alpha-globulins, and 0.23% (52 microM) for human alpha(1)-AGP. K(i) values of bovine serum albumin, bovine alpha-globulins and bovine alpha(1)-AGP were 3-5 times higher than those of the respective human proteins. The results suggest a direct interaction of some of these serum proteins with the active site of the CYP3A isoform. Since the bovine serum proteins showed weaker inhibitory effects than human serum proteins, the wide use of BSA, which is viewed as interchangeable with HSA, needs to be cautioned.

Structure-activity relationship in O-glucuronidation of indolocarbazole analogs.

The glucuronidation of 6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(beta-D-glucopyranosyl)5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (compound 1), a potent inhibitor of DNA topoisomerase I, and its related indolocarbazole compounds was studied using human liver microsomes. Compound 1 and its structurally related compounds with the NHCHO moiety at the N-6 position were glucuronidated even if the positions of the phenolic hydroxy moiety were different in these molecules. Compounds that have the NHCH(CH(2)OH)(2) moiety at the N-6 position, however, were not glucuronidated. The three-dimensional structure of these substrates was determined by the semiempirical molecular-orbitals calculation method. Computer-modeling studies, however, revealed that the O-glucuronidation of indolocarbazole analogs depended on the molecular size of the substrates. Compounds larger than 14.5 A in diameter perpendicular to the phenolic hydroxy moiety were not glucuronidated. The chemical reactivity of the hydroxy moiety, evaluated by the atom electron density and the electrostatic potential charges, was very similar in these substrates. These results suggest that a molecular length less than 14.5 A may be required for a substrate to interact with the active site of UDP-glucuronosyltransferase (UGT). To further characterize the glucuronidation of indolocarbazole analogs, compound 1 was used as a representative compound to assess expressed human UGTs. The glucuronidation of compound 1 was catalyzed by recombinant UGT1A9 and UGT1A10 among UGT isoforms tested.