Multicenter-Based Population Pharmacokinetic Analysis of Ciclosporin in Hematopoietic Stem Cell Transplantation Patients.

PURPOSE: To explore the contribution of physiological characteristics to variability in ciclosporin pharmacokinetics in hematopoietic stem cell transplantation patients. METHODS: Clinical data from 563 patients were collected from centers in three regions. Ciclosporin concentrations were measured using immunoassays. The patients' demographics, hematological and biological indicators, coadministered drugs, region, and disease diagnosis were recorded from medical records. Data analysis was performed using NONMEM based on a one-compartment model to describe the pharmacokinetics of ciclosporin. The reliability and stability of the final model were evaluated using bootstrap resampling, goodness-of-fit plots, and prediction-corrected visual predictive checks. RESULTS: The population estimate of the clearance (CL) was 30.4 L/h, the volume of distribution (V) was 874.0 L and the bioavailability (F) was 81.1%. The between-subject variability in these parameters was 26.3, 68.0, and 110.8%, respectively. Coadministration of fluconazole, itraconazole, or voriconazole decreased CL by 17.6%, 28.4%, and 29.2%, respectively. Females' CL increased by approximately 12.0%. In addition, CL and V decreased with hematocrit, total protein, and uric acid increase, and CL also decreased with age and aspartate aminotransferase increase. However, CL increased with creatinine clearance increase. CONCLUSIONS: A multicenter-based population pharmacokinetic model of ciclosporin was established. The pharmacokinetics of ciclosporin exhibited discrepancies among different regions.

Metabolism and disposition of pyrotinib in healthy male volunteers: covalent binding with human plasma protein.

Pyrotinib is a novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor that is used to treat HER2-positive breast cancer. In this study we investigated the metabolism and disposition of pyrotinib in six healthy Chinese men after a single oral dose of 402 mg of [14C]pyrotinib. At 240 h postdose, the mean cumulative excretion of the dose radioactivity was 92.6%, including 1.7% in urine and 90.9% in feces. In feces, oxidative metabolites were detected as major drug-related materials and the primary metabolic pathways were O-depicoline (M1), oxidation of pyrrolidine (M5), and oxidation of pyridine (M6-1, M6-2, M6-3, and M6-4). In plasma, the major circulating entities identified were pyrotinib, SHR150980 (M1), SHR151468 (M2), and SHR151136 (M5), accounting for 10.9%, 1.9%, 1.0%, and 3.0%, respectively, of the total plasma radioactivity based on the AUC0-∞ ratios. Approximately 58.3% of the total plasma radioactivity AUC0-∞ was attributed to covalently bound materials. After incubation of human plasma with [14C]pyrotinib at 37 °C for 2, 5, 8, and 24 h, the recovery of radioactivity by extraction was 97.4%, 91.8%, 69.6%, and 46.7%, respectively, revealing covalent binding occurred independently of enzymes. A group of pyrotinib adducts, including pyrotinib-lysine and pyrotinib adducts of the peptides Gly-Lys, Lys-Ala, Gly-Lys-Ala, and Lys-Ala-Ser, was identified after HCl hydrolysis of the incubated plasma. Therefore, the amino acid residue Lys190 of human serum albumin was proposed to covalently bind to pyrotinib via Michael addition. Finally, the covalently bound pyrotinib could dissociate from the human plasma protein and be metabolized by oxidation and excreted via feces.

Theory-based pharmacokinetics and pharmacodynamics of S- and R-warfarin and effects on international normalized ratio: influence of body size, composition and genotype in cardiac surgery patients.

AIMS: The aims of this study are to apply a theory-based mechanistic model to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of S- and R-warfarin. METHODS: Clinical data were obtained from 264 patients. Total concentrations for S- and R-warfarin were measured by ultra-high performance liquid tandem mass spectrometry. Genotypes were measured using pyrosequencing. A sequential population PK parameter with data method was used to describe the international normalized ratio (INR) time course. Data were analyzed with NONMEM. Model evaluation was based on parameter plausibility and prediction-corrected visual predictive checks. RESULTS: Warfarin PK was described using a one-compartment model. CYP2C9 *1/*3 genotype had reduced clearance for S-warfarin, but increased clearance for R-warfarin. The in vitro parameters for the relationship between prothrombin complex activity (PCA) and INR were markedly different (A = 0.560, B = 0.386) from the theory-based values (A = 1, B = 0). There was a small difference between healthy subjects and patients. A sigmoid Emax PD model inhibiting PCA synthesis as a function of S-warfarin concentration predicted INR. Small R-warfarin effects was described by competitive antagonism of S-warfarin inhibition. Patients with VKORC1 AA and CYP4F2 CC or CT genotypes had lower C50 for S-warfarin. CONCLUSION: A theory-based PKPD model describes warfarin concentrations and clinical response. Expected PK and PD genotype effects were confirmed. The role of predicted fat free mass with theory-based allometric scaling of PK parameters was identified. R-warfarin had a minor effect compared with S-warfarin on PCA synthesis. INR is predictable from 1/PCA in vivo.

The genetic polymorphisms of POR*28 and CYP3A5*3 significantly influence the pharmacokinetics of tacrolimus in Chinese renal transplant recipients.

PURPOSES: The aims of this study were to assess the influence of the polymorphism of cytochrome P450 oxidoreductase (POR) as well as other relevant genes (CYP3A4, CYP3A5, ABCB1) on individual variability of tacrolimus pharmacokinetics and perform population pharmacokinetic analysis of tacrolimus in Chinese renal transplant recipients. METHODS: Tacrolimus trough whole blood concentrations and clinical details were retrospectively collected from 83 renal recipients. CYP3A4*1G, CYP3A5*3, and ABCB1 C3435T were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), POR*28 and CYP3A4*22 were genotyped by sequencing method. Population pharmacokinetic analysis was performed using NONMEM program. RESULTS: The significant influences of CYP3A5*3, CYP3A4*1G, and POR*28 polymorphisms on tacrolimus dose-adjusted trough concentrations (C0/D) were observed in 83 renal recipients. Subgroup analysis showed that POR*28 polymorphisms significantly decreased tacrolimus C0/D by 1.50 - 1.84-fold (p < 0.05) in patients who were CYP3A5 expressers (CYP3A5*1 carriers, n = 46), while similar results could not be obtained from CYP3A5 non-expressers (CYP3A5*3/*3 carriers, n = 37). Additionally, population pharmacokinetic analysis identified that the combined genotype of CYP3A5-POR was the only covariant for the apparent clearance of tacrolimus (CL/F). CONCLUSIONS: The study demonstrated that the POR*28 C>T mutation could decrease the C0/D of tacrolimus in renal recipients who were CYP3A5 expressers. The population pharmacokinetic model showed that the combined genotype of CYP3A5-POR was associated with the CL/F of tacrolimus which might provide references for personalized use of tacrolimus in clinic.

Population pharmacokinetics and individualized dosage prediction of cyclosporine in allogeneic hematopoietic stem cell transplant patients.

BACKGROUND: Cyclosporine (CsA), a potent immunosuppressive agent used to prevent rejection, is characterized by large individual variability. The purpose of this study was to explore the pharmacokinetic characteristics of CsA and establish a CsA population pharmacokinetic model that could be used for personalized therapy in allogeneic hematopoietic stem cell transplant (allo-HSCT) patients. METHODS: Clinical data were obtained from 117 allo-HSCT patients. The data analysis was performed using NONMEM software. A first-order conditional estimation with interaction (FOCE-I) method within NONMEM was used to estimate the parameters. The covariates, including demographics, hematological indices, biochemical levels, concurrent drugs, and genetic polymorphisms of CYP3A4, CYP3A5, and ABCB1, were evaluated quantitatively. The stability of the final model was validated by a nonparametric bootstrap procedure. RESULTS: A total of 1,571 observed concentrations were collected. A 1-compartment model with first-order absorption and elimination adequately described the pharmacokinetics of CsA. The typical values for clearance (CL), volume of distribution (V), and bioavailability were 29.6 L/hr, 605 L, and 0.619, respectively. The interindividual variability of these parameters was 20.4, 66.1, and 30.4%, respectively. The residual error was 31.4% and 23.7 ng/mL. The duration of CsA therapy, hematocrit, antifungal agent administration, triglycerides, and weight were identified as the main covariates that influenced CL, and hematocrit had a significant effect on V. The internal validation showed that the final model was stable and accurate. CONCLUSIONS: This study established a population pharmacokinetic model of CsA in allo-HSCT patients that could provide the foundation for personalized use of CsA in the clinic.

[Population pharmacokinetics and pharmacodynamics of clopidogrel in patients with acute coronary syndrome].

This study established a population pharmacokinetics-pharmacodynamics model of clopidogrel in patients with acute coronary syndrome. Fifty-nine patients were enrolled. The plasma concentration of clopidogrel active metabolite and vasodilator stimulated phosphoprotein platelet reactivity index (VASP-PRI) were selected as the pharmacokinetics index and the pharmacodynamics index, respectively. The covariates including demographic characteristics, laboratory indexes, combined medication, complications and genetic polymorphisms of related enzymes were screened for their influence on the pharmacokinetic and pharmacodynamics parameters. Population pharmacokinetic and pharmacodynamics data analysis was performed using NONMEM software. The general linear model and the indirectly effect model-turnover model for pharmacokinetic and pharmacodynamic analysis were selected as the basic model, respectively. The population typical values of K12, CL/F, V/F, EC50, K(in), and E(max) were 0.259 h(-1), 179 L x h(-1), 632 L, 1.57 ng x mL(-1), 4.29 and 0.664, respectively. CYP2C19 was the covariate in the final pharmacokinetic model, and the model was to design a prior dosage regimen.

Efficacy and safety of adjunctive cilostazol to dual antiplatelet therapy after stent implantation: an updated meta-analysis of randomized controlled trials.

BACKGROUND: Aspirin and clopidogrel dual antiplatelet therapy (DAT) reduce ischemic events in patients with cardiovascular disease. However, recurrent ischemic event occurrence during DAT remains a major concern. This systematic review assesses the efficacy and safety of adjunctive cilostazol to DAT in combination with DAT on reducing clinical adverse events. METHODS: We searched randomized controlled trials (RCTs) in PubMed, Embase, Cochrane library, clinicaltrial.gov, and Chinese Biomedical Database through July 2011. Pooled risk ratio (RR) with 95% confidence intervals (CIs) was calculated. Two independent reviewers evaluated the included studies. The extracted data were analyzed by Review Manager 5.1.2 (The Cochrane Collaboration, Oxford, UK) and GRADEprofiler 3.6 (GRADE Working Group). RESULTS: A total of 7 RCTs (4351 patients) were included in the analysis, with a follow-up period of 6 to 12 months. Pooled analysis showed that cilostazol was associated with a significant reduction in major adverse cardiac events (MACEs; pooled RR 0.69, 95% CI 0.52-0.91; P = .008) and repeat revascularization (RR 0.74, 95% CI 0.61-0.89; P = .002); however, cilostazol was not associated with a reduction in the risk of stent thrombosis (RR 1.00, 95% CI 0.41-2.45; P = 1.00). Cilostazol seems to be safe, with no significant increase in the risk of bleeding (RR 1.06, 95% CI 0.72-1.56; P = .77). The 4 outcomes were low-quality evidence for MACE, moderate-quality evidence for repeat revascularization, and high-quality evidence for bleeding and stent thrombosis. CONCLUSIONS: When compared to the currently recommended DAT, triple antiplatelet therapy with cilostazol can reduce repeat revascularization with no increase in the risk of bleeding.

Effect of the P450 oxidoreductase 28 polymorphism on the pharmacokinetics of tacrolimus in Chinese healthy male volunteers.

PURPOSE: To assess the influence of the P450 oxidoreductase 28 SNP (POR 28) on tacrolimus pharmacokinetics in the Chinese population. METHODS: Seventy-one healthy Chinese volunteers enrolled in the study received an oral dose of 2 mg of tacrolimus after providing written informed consent. CYP3A5 3 was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and POR*28 was genotyped by PCR-direct sequencing. Tacrolimus whole blood concentrations were determined by ultra performance liquid chromatography-tandem mass spectrometry and the pharmacokinetics analyses was evaluated by nonparametric methods. RESULTS: The frequencies of CYP3A5 3 and POR 28 allele were 73.3 % and 29.6 %, respectively. No significant differences existed in tacrolimus pharmacokinetics between the POR 28 CC homozygotes (n = 32) and the POR 28 T allele (n = 39) in all subjects. The mean tacrolimus AUC0-24, AUC0-∞ and Cmax for the POR 28 CC (n = 14) homozygotes in CYP3A5 expressers (CYP3A5 1/ 1 or 1/ 3 genotype) were 71.5 ± 38.9 h ng/mL, 94.3 ± 58.3 h ng/mL and 17.6 ± 9.8 ng/mL, which were much higher than the POR 28 CT heterozygotes (n = 17) of 46.7 ± 24.9 h ng/mL, 57.4 ± 33.9 h ng/mL and 11.2 ± 6.4 ng/mL (P < 0.05, respectively). We did not observe any significant differences in tacrolimus pharmacokinetics between the POR 28 CC homozygotes (n = 18) and POR 28 T carriers (n = 22) in CYP3A5 nonexpressers (CYP3A5 3/ 3 carriers). CONCLUSIONS: The POR 28 CT genotype presented a significantly lower level of tacrolimus exposure (AUC, Cmax) compared with the POR 28 CC genotype in CYP3A5-expressing subjects. It suggested that the POR 28 genetic polymorphism might also be responsible for the marked interindividual variability of tacrolimus besides the CYP3A5 3 genetic polymorphism.

Mutation-sensitive molecular switch method to detect CES1A2 mutation in the Chinese Han and Yao populations.

Carboxylesterase 1 (CES1) is involved in the metabolic activation of a variety of prodrugs into active derivatives and plays an important role in pharmacokinetics and pharmacodynamics. A single-nucleotide polymorphism, A(-816)C, of the CES1A2 gene has been shown to enhance transcription efficiency and increase enzyme activity. The aim of this study was to develop an easy method to detect this polymorphism. For this we used the mutation-sensitive molecular switch method to investigate the polymorphism distribution in the Chinese Han and Yao populations. The method was well validated by direct sequencing. In 204 Han individuals, the percentages of the distribution of CES1A2 A(-816)C genotypes are AA 58.33% (n=119), AC 35.78% (n=73), and CC 5.88% (n=12). The genotype frequencies are AA 47.76% (n=96), AC 42.79% (n=86), and CC 9.45% (n=19) in 201 Yaos. The frequency of the mutant C allele in the Yao population is significantly higher than that in the Han population (30.85% vs. 23.77%, p=0.0239). The method can be easily used for the detection of the single-nucleotide polymorphism in CES1A2, and we found that there is a marked difference in mutant C allele between Chinese Han and Yao populations, suggesting individual and ethnic differences of CES1 drug metabolism between these two populations.

1-[(6-Chloro-3-pyrid-yl)meth-yl]-N-(4-ethoxy-phen-yl)-3-phenyl-1H-pyrazole-5-carboxamide.

In the title compound, C(24)H(21)ClN(4)O(2), the pyrazole ring makes dihedral angles of 7.70 (11), 89.17 (11) and 40.68 (11)° with the phenyl, pyridine and ethoxy-phenyl rings, respectively. There are some intra-molecular C-H⋯O and C-H⋯π bonds giving rigidity to the mol-ecule, while weak inter-molecular N-H⋯N and C-H⋯π hydrogen bonds link the mol-ecules into a two-dimensional structure.