Pei Hu

Evaluating a physiologically based pharmacokinetic model for prediction of omeprazole clearance and assessing ethnic sensitivity in CYP2C19 metabolic pathway

PurposeThe purpose of this study is to evaluate the ethnicity-specific population models in the SimCYP Simulator® for prediction of omeprazole clearance with attention to differences in the CYP2C19 metabolic pathway.MethodsThe SimCYP® models incorporating Caucasian, Chinese, and Japanese population-specific demographic, physiological, and enzyme data were applied to simulate omeprazole pharmacokinetics. Published pharmacokinetic data of omeprazole after intravenous or oral administration in Caucasian, Chinese, and Japanese were used for the evaluation.ResultsFollowing oral administration, the ratio of the predicted to observed geometric mean of omeprazole clearance in Caucasian extensive metabolizers (EMs) was 0.88. The ratios in Chinese EMs were 1.16 and 0.99 after intravenous and oral administration, respectively. The ratios in Japanese EMs were 0.88 and 0.71 after intravenous and oral administration, respectively.Significant differences (2-fold) in the observed oral clearance of omeprazole were identified between Caucasian and Asian (Chinese and Japanese) EMs while the observed oral and intravenous clearances of omeprazole were similar between Chinese and Japanese EMs. Physiologically based pharmacokinetics (PBPK) models within SimCYP accurately predicted the difference in the observed oral clearance between Caucasian and Chinese EMs but overpredicted the difference between Caucasians and Japanese EMs due to under-prediction of oral clearance in Japanese EMs.ConclusionsThe PBPK model within SimCYP adequately predicted omeprazole clearance in Caucasian, Chinese, and Japanese EMs and the 2-fold differences in clearance of omeprazole between Caucasian and Asian EMs. This may lead to early identification of ethnic sensitivity in clearance and the need for different dosing regimens in a specific ethnic group for substrates of CYP2C19 which can support the rational design of bridging clinical trials.

Quantitative prediction of human pharmacokinetics and pharmacodynamics of imigliptin, a novel DPP-4 inhibitor, using allometric scaling, IVIVE and PK/PD modeling methods.

PURPOSEnTo predict the pharmacokinetic/pharmacodynamic (PK/PD) profiles of imigliptin, a novel DPP-4 inhibitor, in first-in-human (FIH) study based on the data from preclinical species.nnnMETHODSnImigliptin was intravenously and orally administered to rats, dogs, and monkeys to assess their PK/PD properties. DPP-4 activity was the PD biomarker. PK/PD profiles of sitagliptin and alogliptin in rats and humans were obtained and digitized from literatures. PK/PD profiles of all dose levels for each drug in each species were analyzed using modeling approach. Human CL, Vss and PK profiles of imigliptin were then predicted using Allometric Scaling (AS), in vitro in vivo extrapolation (IVIVE), and the steady-state plasma drug concentration - mean residence time (Css-MRT) methods. In vitro EC50 corrected by fu and in vivo EC50 in rats corrected by interspecies difference of sitagliptin and alogliptin were utilized separately to predict imigliptin human EC50. The prediction by integrating all above methods was evaluated by comparing observed and simulated PK/PD profiles in healthy subjects.nnnRESULTSnFull PK/PD profiles in animal were summarized for imigliptin, sitagliptin and alogliptin. Imigliptin CL, Vss, and Fa were predicted to be 19.1L/h, 247L, and 0.81 in humans, respectively. Predicted imigliptin AUCs, AUECs, and Emax in humans were within 0.8-1.2 times of observed values whereas other predicted PK/PD parameters were within 0.5-1.5 times of observed values.nnnCONCLUSIONSnBy integrating available preclinical and clinical data, FIH PK/PD profiles of imigliptin could be accurately predicted.

Combining 'Bottom-Up' and 'Top-Down' Methods to Assess Ethnic Difference in Clearance: Bitopertin as an Example.

AbstractBackground and ObjectivesWe propose a strategy for studying ethnopharmacology by conducting sequential physiologically based pharmacokinetic (PBPK) prediction (a ‘bottom-up’ approach) and population pharmacokinetic (popPK) confirmation (a ‘top-down’ approach), or in reverse order, depending on nwhether the purpose is ethnic effect assessment for a new molecular entity under development or a tool for ethnic sensitivity prediction for a given pathway. The strategy is exemplified with bitopertin.MethodsA PBPK model was built using Simcyp® to simulate the pharmacokinetics of bitopertin and to predict the ethnic sensitivity in clearance, given pharmacokinetic data in just one ethnicity. Subsequently, a popPK model was built using NONMEM® to assess the effect of ethnicity on clearance, using human data from multiple ethnic groups. A comparison was made to confirm the PBPK-based ethnic sensitivity prediction, using the results of the popPK analysis.ResultsPBPK modelling predicted that the bitopertin geometric mean clearance values after 20xa0mg oral administration in Caucasians would be 1.32-fold and 1.27-fold higher than the values in Chinese and Japanese, respectively. The ratios of typical clearance in Caucasians to the values in Chinese and Japanese estimated by popPK analysis were 1.20 and 1.17, respectively. The popPK analysis results were similar to the PBPK modelling results.ConclusionAs a general framework, we propose that PBPK modelling should be considered to predict ethnic sensitivity of pharmacokinetics prior to any human data and/or with data in only one ethnicity. In some cases, this will be sufficient to guide initial dose selection in different ethnicities. After clinical trials in different ethnicities, popPK analysis can be used to confirm ethnic differences and to support dose justification and labelling. PBPK modelling prediction and popPK analysis confirmation can complement each other to assess ethnic differences in pharmacokinetics at different drug development stages.

Effects of four traditional Chinese medicines on the pharmacokinetics of simvastatin

Abstract 1.u2002Concomitant traditional Chinese medicines (TCMs) could be the reason for relative poor efficacy of statins in dyslipidemia patients in China. 2.u2002An open-label, randomized, 5-period crossover study in healthy Chinese was designed to evaluate the pharmacokinetic interaction and tolerability of multiple doses of certain TCMs on a single dose of simvastatin. In each period, subjects received one of five treatments. In Treatment A, subjects received a single dose of 20u2009mg simvastatin. In Treatment B, C, D or E, subjects received Tong Xin Luo, Nao Xin Tong, Guan Mai Ning or Yin Xing Ye for 7 days and a single dose of 20u2009mg simvastatin on Day 7. The washout period was 7 days. 3.u2002The 97.5% confidence interval of the AUC0–48u2009h geometric mean ratio of simvastatin acid and simvastatin for simvastatin given after multiple oral doses of one of the TCMs versus simvastatin given alone were fully contained within the prespecified bounds of (0.50, 2.00). 4.u2002Exposures to simvastatin acid and simvastatin following a single dose of simvastatin alone were similar to those following coadministration of a single dose of simvastatin with multiple doses of each of the TCM preparations tested. Simvastatin and these TCMs were well tolerated.

CYP2D6 Phenotyping Using Urine, Plasma, and Saliva Metabolic Ratios to Assess the Impact of CYP2D6∗10 on Interindividual Variation in a Chinese Population

Purpose: Asian populations have around 40–60% frequency of reduced function allele CYP2D6∗10 compared to 1–2% in Caucasian populations. The wide range of CYP2D6 enzyme activities in subjects with the CYP2D6∗10 variant is a big concern for clinical practice. The quantitative analysis measuring the impact of CYP2D6 enzyme activity as a result of one CYP2D6∗10 allele or two CYP2D6∗10 alleles has not been reported in large Asian populations. Methods: A total of 421 healthy Chinese subjects were genotyped for CYP2D6 by polymerase chain reaction and direct DNA sequencing. A total of 235 subjects with CYP2D6∗1/∗1 (n = 22), CYP2D6∗1/∗10 (n = 93), CYP2D6∗10/∗10 (n = 85), and CYP2D6∗5/∗10 (n = 35) were phenotyped for CYP2D6 using dextromethorphan as the probe drug. Metabolic ratios (MR) were calculated as the ratio of parent drug to metabolite in 0–3 h urine, 3 h plasma, and 3 h saliva for each sample type. Results: The urinary, plasma, or salivary MRs increased successively in subjects with CYP2D6∗1/∗1, ∗1/∗10, ∗10/∗10, and ∗5/∗10 (all P < 0.001). In the normal metabolizer group, homozygous CYP2D6∗10/∗10 decreased the CYP2D6 enzyme activity further than heterozygous CYP2D6∗1/∗10. Urinary, plasma, and salivary MRs were highly correlated. Conclusion: The normal metabolizer group calls for a more detailed classification. The activity score system could more accurately predict enzyme activity than by grouping a number of genotypes into a single phenotype group. Single-point plasma samples and saliva samples could be used as alternative phenotyping methods for clinical convenience.

Pharmacokinetics and pharmacodynamics of intravenous ilaprazole in healthy subjects after single ascending doses.

Abstract 1.u2003Ilaprazole is a novel proton pump inhibitor and this is the first study to investigate the pharmacokinetics, pharmacodynamics and safety of intravenous ilaprazole in healthy volunteers. 2.u2003In this open-label, single-dose, randomized and four-period crossover study, 16 healthy Chinese subjects received ilaprazole 5, 10 or 20u2009mg intravenously, or 10u2009mg orally. Serial blood and urine samples were collected and intragastric pH was recorded within 24u2009h. The percentage time of intragastric pHu2009>u20096 was the major index. Safety was assessed throughout the study. 3.u2003Plasma exposure of intravenous ilaprazole increased proportionally over the dose of 5–20u2009mg. Clearance and volume of distribution were independent of dose. Ilaprazole was not eliminated through urine and the absolute bioavailability was 55.2%. For the intravenous dose of 5, 10, 20u2009mg, and oral dose of 10u2009mg, the mean percentages time of intragastric pHu2009>u20096 were 47.3%, 52.8%, 68.2% and 47.5%, respectively. 4.u2003Ilaprazole showed linear pharmacokinetics over the dose of 5–20u2009mg. Intravenous ilaprazole provided rapid onset of action and the potency of effect were exhibited in a dose-dependent manner. Intravenous ilaprazole was safe and well tolerated except for elevated activated partial thromboplastin time (APTT) and prothrombin time (PT).

Investigation of a potential pharmacokinetic interaction between perindopril arginine and amlodipine when administered as a single perindopril/amlodipine fixed-dose combination tablet in healthy Chinese male volunteers.

OBJECTIVESnTo determine whether a potential pharmacokinetic interaction exists between perindopril arginine 5 mg and amlodipine 5 mg, after administration as a fixed-combination of perindopril 5 mg/amlodipine 5 mg (S05985).nnnMETHODSnA total of 30 subjects was enrolled into this single center, open-label, randomized, 3-period cross-over study and was randomized to receive 1 tablet of S05985, 1 tablet of perindopril tert-butylamine 4 mg, or 1 tablet of amlodipine 5 mg. The doses of both perindopril salts correspond to 3.34 mg of perindopril expressed as free acid. Serial blood samples were collected in each treatment period for determination of plasma amlodipine, perindopril, and perindoprilat concentrations and for calculation of the respective pharmacokinetic parameters (AUC(0-∞), AUC(0-t), C(max), and t(max)). Statistical analyses of the pharmacokinetic parameters included ANOVA and calculations of 90% confidence intervals for the ratio of the geometric means for Cmax, AUC(0-t), and AUC(0-∞). Safety was also assessed.nnnRESULTSnA total of 29 subjects completed the study per protocol. There was no serious adverse event. All 90% confidence intervals for C(max), AUC(0-t), and AUC(0-∞) for perindopril, perindoprilat, and amlodipine were within the limits (80.00 - 125%), indicating that both treatments were bioequivalent.nnnCONCLUSIONnThese results indicate that no drug-drug interaction exists after single-dose oral administration of S05985 (perindopril 5 mg and amlodipine 5 mg) when compared to single-dose administration of each component alone, i.e., perindopril tert-butylamine 4 mg and amlodipine 5 mg, given separately.

Pharmacokinetics and Safety of Tedizolid after Single and Multiple Intravenous/Oral Sequential Administrations in Healthy Chinese Subjects

PURPOSEnTedizolid phosphate is a new antibacterial agent under investigation for the treatment of Gram-positive infections in China. This study was conducted to assess the pharmacokinetic (PK) properties, oral bioavailability, and safety of once daily tedizolid phosphate 200 mg in Chinese subjects to support its further clinical development in China.nnnMETHODSnThis Phase I single-center study, conducted in 16 healthy Chinese male subjects, consisted of a single-dose administration, 1:1 randomized, two-way, intravenous (IV)/oral (PO) crossover of tedizolid phosphate 200 mg (Part 1) and, after a 7-day washout, a nonrandomized, multiple-dose, 7-day tedizolid phosphate 200 mg once daily administration (IV for 3 days, PO for 4 days; Part 2). Blood samples were collected for up to 72 hours after single dosing and for up to 2 hours on Day 3 and 72 hours on Day 7 of multiple dosing to determine PK parameters. Adverse events (AEs) were recorded throughout the entire study.nnnFINDINGSnThe Cmax and AUC of tedizolid (the active moiety of tedizolid phosphate) were 3.02 µg/mL and 30.50 µg • h/mL after single IV dosing of tedizolid phosphate, and 2.25 µg/mL and 26.10 µg • h/mL after single PO dosing, respectively, and the mean half-life was 10.1 hours for both administration routes. The oral bioavailability of tedizolid was 85.5%. PK parameters of tedizolid were similar after single and multiple dosing of tedizolid phosphate, indicating no time dependency. Only minor accumulation of tedizolid was observed after multiple dosing (expressed as accumulation ratios RAAUC: 1.18 for PO dosing, and RACmax: 1.16 and 1.05 for IV and PO dosing, respectively). Steady state of tedizolid was reached after about 3 days, and trough concentrations remained constant when switching from IV to PO dosing. Tedizolid phosphate was well tolerated with 6 subjects (37.5%) in Part 1 and 5 subjects (31.3%) in Part 2 experiencing an AE; all AEs but one were related to the study drug assessed by the investigator. All AEs were of mild intensity and had recovered or resolved by the end of the study. No serious AEs were observed, and no subjects prematurely discontinued the study due to an AE.nnnIMPLICATIONSnThe results of this Phase I study conducted in Chinese male subjects indicate that no dosage adjustment of tedizolid phosphate 200 mg would be required when switching administration routes in this population. Tedizolid phosphate was well tolerated in healthy Chinese subjects. China Food and Drug Administration clinical trial permission numbers 2014L00360 and 2014L00361.

Cytochrome P450 2D6 genotype affects the pharmacokinetics of controlled-release paroxetine in healthy Chinese subjects: comparison of traditional phenotype and activity score systems.

PurposeThis study evaluated the effects of cytochrome P450 (CYP) 2D6 polymorphisms on the pharmacokinetics of controlled-release paroxetine in healthy Chinese subjects and used paroxetine as a tool drug to compare the performance of traditional phenotype and activity score systems.MethodsPharmacokinetic data were evaluated in 24 subjects who received a single oral dose of 25xa0mg controlled-release paroxetine. Plasma paroxetine concentrations were measured by LC-MS/MS. CYP2D6 genotypes were tested by PCR and direct DNA sequencing. Subjects were classified by two systems of phenotype prediction. In the traditional phenotype system, subjects were classified as extensive metabolizers or intermediate metabolizers; in the activity score system, subjects were divided into four activity groups. Analysis of variance testing was applied to estimate the effects of CYP2D6 polymorphisms on the pharmacokinetics of paroxetine.ResultsWith the traditional phenotype system, significant differences were observed in the following pharmacokinetic parameters of paroxetine: t1/2, Cmax, AUC0–t, AUC0–inf, Vz/F, and CL/F (all Pu2009<u20090.05). The AUC or exposure of paroxetine was about 3.5-fold higher in the intermediate metabolizer group than in the extensive metabolizer group. With the activity score system, significant differences were observed in the t1/2, Cmax, AUC0–t, AUC0–inf, Vz/F, and CL/F among the four different activity score groups (all Pu2009<u20090.05). We found that the AUC of paroxetine decreased by around one half as the activity score increased by 0.5.ConclusionThe pharmacokinetics of controlled-release paroxetine after a single administration was affected by CYP2D6 polymorphisms. Both the traditional phenotype and the activity score systems performed well and distinguished subjects with different drug exposures. The activity score system provided a more detailed classification for the subjects.

Development of an UPLC-MS/MS method for quantification of Avitinib (AC0010) and its five metabolites in human cerebrospinal fluid: Application to a study of the blood-brain barrier penetration rate of non-small cell lung cancer patients.

HIGHLIGHTSAvitinib (AC0010) is a novel mutant‐selective EGFR‐TKI that shows a good curative effect on NSCLC patients.Up to now, there has been no publication of determination method for Avitinib.Cerebrospinal fluid is a special matrix for which method development is difficult.The method determined not only the parent Avitinib, but also its five metabolites at the same time.The method successfully applied to the BBB penetration rate research of Avitinib for advanced NSCLC patients with metastatic encephaloma. ABSTRACT Avitinib (AC0010) is a mutant‐selective epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKI), designed to be a targeted therapeutic agent for non‐small cell lung cancer (NSCLC) patients harboring EGFR active and T790M resistant mutations. A rapid and sensitive ultra‐performance liquid chromatography‐tandem mass spectrometry (UPLC‐MS/MS) method was developed and validated for the determination of Avitinib and its five metabolites (M1, M2, M4, M7, MII‐6) in human cerebrospinal fluid (CSF). The samples were purified by protein precipitation and separated on a BEH C18 column (2.1 × 50 mm, 1.7 &mgr;m). Electrospray ionization (ESI) in positive ion mode and multiple reaction monitoring (MRM) were used to monitor the ion transitions at m/z 488/257, 474/403, 504/487, 434/377, 490/405, 476/391. The results indicated that the method had excellent sensitivity and specificity. The linear range covered from 0.05 to 50 ng/mL for Avitinib, M1, M4, M7, and MII‐6, and from 0.01 to 10 ng/mL for M2. Intra‐day and inter‐day precisions (in terms of% RSD) were all <15% and the accuracies (in terms of% RE) were within the range of ±15%. The lower limit of quantification (LLOQ), matrix effect, extraction recovery, stability and dilution integrity were also validated and satisfied with the criteria of validation. Finally, the method was successfully applied to a blood‐brain barrier (BBB) penetration rate research of NSCLC patients after an oral administration of Avitinib.