Journal of Clinical Pharmacology最新文献

Continuous infusion of meropenem is a candidate strategy for optimization of its pharmacokinetic/pharmacodynamic profile. However, plasma concentrations are difficult to predict in critically ill patients. Steady-state concentrations of meropenem were determined prospectively during continuous infusion in 32 surgical ICU patients (aged 21-85 years, body weight 55-125 kg, APACHE II 5-29, measured creatinine clearance 22.7-297 mL/min). Urine was collected for the quantification of renal clearance of meropenem and creatinine. Cystatin C was measured as an additional marker of renal function. Population pharmacokinetic models were developed using NONMEM(®) , which described total meropenem clearance and its relationship with several estimates of renal function (measured creatinine clearance CLCR , Cockcroft-Gault formula CLCG , Hoek formula, 1/plasma creatinine, 1/plasma cystatin C) and other patient characteristics. Any estimate of renal function improved the model performance. The strongest association of clearance was found with CLCR (typical clearance = 11.3 L/h × [1 + 0.00932 × (CLCR  - 80 mL/min)]), followed by 1/plasma cystatin C; CLCG was the least predictive covariate. Neither age, weight, nor sex was found to be significant. These models can be used to predict dosing requirements or meropenem concentrations during continuous infusion. The covariate CLCR offers the best predictive performance; if not available, cystatin C may provide a promising alternative to plasma creatinine.

This crossover study investigated the pharmacokinetics and adverse effects of high-dose intravenous melatonin. Volunteers participated in 3 identical study sessions, receiving an intravenous bolus of 10 mg melatonin, 100 mg melatonin, and placebo. Blood samples were collected at baseline and 0, 60, 120, 180, 240, 300, 360, and 420 minutes after the bolus. Quantitative determination of plasma melatonin concentrations was performed using a radioimmunoassay technique. Pharmacokinetic parameters were estimated by a compartmental pharmacokinetic analysis. Adverse effects included assessments of sedation and registration of other symptoms. Sedation, evaluated as simple reaction times, was measured at baseline and 120, 180, 300, and 420 minutes after the bolus. Twelve male volunteers completed the study. Median (IQR) Cmax after the bolus injections of 10 mg and 100 mg of melatonin were 221,500.0 (185,637.5-326,175.0) pg/mL and 1,251,500.0 (864,375.0-1,770,500.0) pg/mL, respectively; mean (SD) t1/2 was 42.3 (5.6) minutes and 46.2 (6.2) minutes; mean (SD) Vd was 1.6 (0.9) L/kg and 2.0 (0.8) L/kg; mean (SD) CL was 0.0253 (0.0096) L/min · kg and 0.0300 (0.0120) L/min · kg; and median (IQR) AUC0- ∞ , 8,997,633.0 (6,071,696.2-11,602,811.9) pg · min/mL and 54,685,979.4 (36,028,638.6-105,779,612.0) pg · min/mL. High-dose intravenous melatonin did not induce sedation, evaluated as simple reaction times. No adverse effects were reported in the study.

Hydroxyurea (HU) is a crucial therapy for children with sickle cell anemia, but its off-label use is a barrier to widespread acceptance. We found HU exposure is not significantly altered by liquid vs capsule formulation, and weight-based dosing schemes provide consistent exposure. HU is recommended for all children starting as young as 9 months of age with sickle cell anemia (SCA; HbSS and HbSβspan(0) thalassemia); however; a paucity of pediatric data exists regarding the pharmacokinetics (PK) or the exposure-response relationship of HU. This trial aimed to characterize the PK of HU in children and to evaluate and compare the bioavailability of a liquid vs capsule formulation. This multicenter; prospective; open-label trial enrolled 39 children with SCA who provided 682 plasma samples for PK analysis following administration of HU. Noncompartmental and population PK models are described. We report that liquid and capsule formulations of HU are bioequivalent; weight-based dosing schemes provide consistent drug exposure; and age-based dosing schemes are unnecessary. These data support the use of liquid HU in children unable to swallow capsules and in those whose weight precludes the use of fixed capsule formulations. Taken with existing safety and efficacy literature; these findings should encourage the use of HU across the spectrum of age and weight in children with SCA; and they should facilitate the expanded use of HU as recommended in the National Heart; Lung; and Blood Institute guidelines for individuals with SCA.

Combination chemotherapy with platinum and taxane is the first-line treatment for ovarian cancer. The dose-limiting toxicities of these drugs include neuropathy, leukopenia, and neutropenia, but they exhibit substantial interindividual variability. This study investigated the relationship between CYP3A5 polymorphisms and paclitaxel/carboplatin-induced toxicity in Chinese epithelial ovarian cancer patients. Seventy-five patients with epithelial ovarian cancer were recruited. After combination chemotherapy, genotype analysis was conducted, and toxic effects were evaluated according to the Common Toxicity Criteria. A significant association was found between myelosuppression and the CYP3A5*3 genotype. CYP3A5*3/*1 patients showed a significantly higher risk of developing leukopenia (P < .001; Pearson's χ(2) test) and neutropenia (P < .001; Pearson's χ(2) test) than CYP3A5*3*3 patients. CYP3A5*3/*3 patients had significantly higher median leukocyte and neutrophil nadir counts than CYP3A5*3*1 patients (P < .001, Mann-Whitney U test). However, we did not observe an association between neuropathy and CYP3A5*3 in this study (P =.64; Pearson's χ(2) test). This is the first study to verify the influence of CYP3A5 polymorphisms on paclitaxel/carboplatin-induced toxicity in Chinese epithelial ovarian cancer patients. Our findings suggest that interindividual variability in paclitaxel/carboplatin-induced myelosuppression can be predicted by CYP3A5*3 genotyping and that incorporation of CYP3A5*3 genetic data in treatment selection could help to reduce myelosuppression events, thereby individualizing paclitaxel/carboplatin pharmacotherapy.

Recent experimental data suggest bumetanide as a possible therapeutic option in newborn infants with seizures after birth asphyxia. Because pharmacokinetic (PK) data are lacking in this population, who very often benefit from therapeutic cooling, which can modify the PK behavior of a drug, a PK study was conducted in term infants with seizures caused by hypoxic-ischemic encephalopathy. Fourteen infants were included, 13 of them being cooled. Forty-nine blood samples were available for the determination of the plasma concentration of bumetanide. Concentration-time data were analyzed by the use of a population approach performed with Monolix Software. Bumetanide was found to follow a 2-compartment model. The mean values were 0.063 L/h for clearance, 0.28 and 0.44 L for the central and peripheral distribution volumes, respectively, and 0.59 L/h for the distribution clearance. Birth body weight explained the interindividual variability of bumetanide clearance via an allometric model. No relationship was found between bumetanide exposure and its efficacy (reduction in seizure burden) or its toxicity (hearing loss). This study describes the first PK model of bumetanide in hypothermia-treated infants with seizures.

The pharmacokinetics (PK) and safety of single-dose buparlisib (30 mg) were assessed in subjects with mild to severe hepatic impairment (n = 6 each) relative to healthy controls (n = 13). Blood samples were collected until 336 hours postdose and evaluated by liquid chromatography tandem mass spectrometry. PK parameters (including area under the curve [AUC∞ ] and Cmax ) were derived using noncompartmental analysis. Buparlisib was rapidly absorbed in all groups (median Tmax 1.0-1.3 h). Buparlisib exposure (AUC∞ ) was moderately increased in subjects with mild (geometric mean ratio [GMR] 1.16; 90%CI 0.81, 1.65), moderate (GMR 1.14; 90%CI 0.80, 1.63), or severe (GMR 1.20; 90%CI 0.84, 1.72) hepatic impairment, relative to healthy controls. Apparent oral clearance was similar across groups. Due to a higher unbound fraction in the severe group (0.21) than all other groups (0.17), subjects with severe hepatic impairment had greater exposure to unbound buparlisib (GMR relative to healthy controls: AUC∞ 1.52; 90%CI 1.09, 2.13; Cmax 1.83; 90%CI 1.42, 2.36). The results indicate that a buparlisib dose adjustment may not be necessary for patients with mild to moderate hepatic impairment. The safety and therapeutic indices should be considered before determining if a dose adjustment is appropriate for patients with severe hepatic impairment.

This multiple-ascending-dose study investigated safety, tolerability, pharmacokinetics, and pharmacodynamics, of macitentan, a new endothelin receptor antagonist (ERA) with sustained receptor binding and enhanced tissue penetration properties compared to other ERAs. Healthy male subjects (n = 32) received once daily oral doses of macitentan (1 - 30 mg) or placebo for 10 days. Administration of macitentan was safe and well tolerated. Macitentan had no effect on bile salts, suggesting an improved liver safety profile. The multiple-dose pharmacokinetics of macitentan were dose-proportional and were characterized by a median tmax and apparent elimination half-life varying from 6.0 to 8.5 and 14.3 to 18.5 hours, respectively, for the different doses and minimal accumulation. ACT-132577, a metabolite with lower potency than macitentan, had a half-life of about 48 hours and accumulated approximately 8.5-fold. Compared to placebo, administration of macitentan caused a dose-dependent increase in plasma ET-1 with maximum effects attained at 10 mg. A small dose-dependent increase in the 6β-hydroxycortisol/cortisol urinary excretion ratio was observed, although there were no statistically significant differences between treatments including placebo. Effects of macitentan on cytochrome P450 enzyme 3A4 should be further evaluated in dedicated studies. The present results support investigation of macitentan in the management of pulmonary arterial hypertension and ET-1-dependent pathologies.

Ceftaroline, the active form of ceftaroline fosamil, is a broad-spectrum cephalosporin antibiotic. A population pharmacokinetic (PPK) model for ceftaroline was developed in NONMEM® using data from 185 healthy subjects and 92 patients with acute bacterial skin and skin structure infection (ABSSSI). Data from 128 patients with community-acquired bacterial pneumonia (CABP) were used for external model validation. Healthy subjects received 50-2,000 mg ceftaroline fosamil via intravenous (IV) infusion over 1 hour or intramuscular (IM) injection q12h or q24h. ABSSSI and CABP patients received 600 mg of ceftaroline fosamil IV over 1 hour q12h. A three-compartment model with zero-order IV or parallel first-order IM input and first-order elimination described ceftaroline fosamil PK. A two-compartment model with first-order conversion of prodrug to ceftaroline and parallel linear and saturable elimination described ceftaroline PK. Creatinine clearance was the primary determinant of ceftaroline exposure. Good agreement between the observed data and both population (r(2)  = 0.93) and individual post-hoc (r(2)  = 0.98) predictions suggests the PPK model can adequately approximate ceftaroline PK using covariate information. Such a PPK model can evaluate dose adjustments for patients with renal impairment and generate ceftaroline exposures for use in pharmacokinetic-pharmacodynamic assessments of efficacy in patients with ABSSSI or CABP.

To characterize doxylamine pharmacokinetics in children. This study was conducted in 41 subjects, ages 2-17 years. Doxylamine succinate doses based on age/weight ranged from 3.125 to 12.5 mg. A single oral dose was administered with 2 to 4 oz. of water or decaffeinated beverages ∼2 hours after a light breakfast. Plasma samples were obtained before and for 72 hours after dosing and analyzed for doxylamine using HPLC MS/MS. Pharmacokinetic parameters were estimated using non-compartmental methods and relationships with age were assessed using linear regression. Over the fourfold dose range, Cmax was similar while AUC increased only 60%, although not statistically significant (P-value = 0.0517). As expected due to increasing body size, CLo and Vz /F increased with age. Due to a similar increase with age for Clo and Vz /F, no age-related differences in t1/2,z were observed (∼16 hours). Allometric scaling indicated no maturation related changes in CLo ; although Vz /F remained age-dependent, the predicted range decreased ∼70%. Overall, the single doses were well tolerated. Somnolence was the most common reported AE with no apparent differences in incidence noted with age. An age/weight dosing nomogram utilizing a fourfold range of doses achieves similar Cmax , whereas AUC increases only 60%.

Studies of liver transplant (LT) patients, mainly in Asians, have evaluated the influence of the CYP3A5*1 allele and P-glycoprotein gene ABCB1 on tacrolimus pharmacokinetics or biopsy-proven acute rejection (BPAR) incidence, with no conclusive results. To investigate these issues, 98 Caucasian Spanish LT patients with tacrolimus, mycophenolate mofetil and steroids and 88 cadaveric donors were genotyped for the SNPs CYP3A5 6986G>A, ABCB1 1236C>T, ABCB1 2677G>A/T and ABCB1 3435C>T;. On day 7 post-LT, patients with a native CYP3A5*1 allele had significantly lower tacrolimus trough concentrations C0 (P = .03) and dose-adjusted concentrations C0 /D (P = .02) than CYP3A5 *3/*3 homozygotes. Three months post-LT, patients carrying a liver with CYP3A5*1 had significantly lower C0 /D (P = .03) and took significantly higher tacrolimus doses (P = .03) than the corresponding *3/*3 homozygotes. ABCB1 SNPs showed no significant association with tacrolimus variables. The 3-month incidence of BPAR was 10.2%, with no statistically significant differences related to CYP3A5 (14.3% in expresser vs. 9.5% in non-expresser) or ABCB1 genotype of either patient or donor. We conclude that in Caucasian Spanish LT patients, a native or graft-borne CYP3A5*1 allele tends to lower tacrolimus concentrations and increase dosage needs, but has no significant impact on the incidence of BPAR.