Population Pharmacokinetic Analysis of Yimitasvir in Chinese Healthy Volunteers and Patients With Chronic Hepatitis C Virus Infection

Yimitasvir is a novel, oral hepatitis C virus (HCV) non-structural protein 5A inhibitor for the treatment of chronic HCV genotype 1 infection. The objective of this analysis was to develop a population pharmacokinetic model of yimitasvir in Chinese healthy volunteers and HCV infection patients. The model was performed using data from 219 subjects across six studies. Nonlinear mixed effects models were developed using Phoenix NLME software. The covariates were evaluated using a stepwise forward inclusion (p < 0.01) and then a backward exclusion procedure (p < 0.001). A two-compartment model with sequential zero-first order absorption and first-order elimination reasonably described yimitasvir pharmacokinetics (PK). The apparent oral clearance and central volume of distribution were 13.8 l·h−1 and 188 l, respectively. The bioavailability (F) of yimitasvir decreased 12.9% for each 100 mg dose increase. Food was found to affect absorption rate (Ka) and F. High-fat meal decreased Ka and F by 90.9% and 38.5%, respectively. Gender and alanine aminotransferase were identified as significant covariates on apparent oral clearance. Female subjects had lower clearance than male subjects. Zero-order absorption duration was longer in healthy volunteers (2.17 h) than that in patients (1.43 h). The population pharmacokinetic model described yimitasvir PK profile well. Food decreased Ka and F significantly, so it was recommended to take yimitasvir at least 2 h before or after a meal. Other significant covariates were not clinically important.

Flavoured water consumption alters pharmacokinetic parameters and increases exposure of erlotinib and gefitinib in a preclinical study using Wistar rats

Background Erlotinib (ERL) and Gefitinib (GEF) are considered first line therapy for the management of non-small cell lung carcinoma (NSCLC). Like other tyrosine kinase inhibitors (TKIs), ERL and GEF are mainly metabolized by the cytochrome P450 (CYP450) CYP3A4 isoform and are substrates for transporter proteins with marked inter-/intra-individual pharmacokinetic (PK) variability. Therefore, ERL and GEF are candidates for drug-drug and food-drug interactions with a consequent effect on drug exposure and/or drug-related toxicities. In recent years, the consumption of flavoured water (FW) has gained in popularity. Among multiple ingredients, fruit extracts, which might constitute bioactive flavonoids, can possess an inhibitory effect on the CYP450 enzymes or transporter proteins. Therefore, in this study we investigated the effects of different types of FW on the PK parameters of ERL and GEF in Wistar rats. Methods ERL and GEF PK parameters in different groups of rats after four weeks consumption of different flavours of FW, namely berry, peach, lime, and pineapple, were determined from plasma drug concentrations using ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). Results Data indicated that tested FWs altered the PK parameters of both ERL and GEF differently. Lime water had the highest impact on most of ERL and GEF PK parameters, with a significant increase in Cmax (95% for ERL, 58% for GEF), AUC0–48 (111% for ERL, 203% for GEF), and AUC0–∞ (200% for ERL, 203% for GEF), along with a significant decrease in the apparent oral clearance of both drugs (65% for ERL, 67% for GEF). The order by which FW affected the PK parameters for ERL and GEF was as follows: lime > pineapple > berry > peach. Conclusion The present study indicates that drinking FW could be of significance in rats receiving ERL or GEF. Our results indicate that the alteration in PKs was mostly recorded with lime, resulting in an enhanced bioavailability, and reduced apparent oral clearance of the drugs. Peach FW had a minimum effect on the PK parameters of ERL and no significant effect on GEF PKs. Accordingly, it might be of clinical importance to evaluate the PK parameters of ERL and GEF in human subjects who consume FW while receiving therapy.

Fosamprenavir with Ritonavir Pharmacokinetics during Pregnancy

ABSTRACT The purpose of this study was to evaluate the pharmacokinetics of ritonavir-boosted fosamprenavir during pregnancy and postpartum. Amprenavir (the active moiety of fosamprenavir) and ritonavir intensive pharmacokinetic evaluations were performed at steady state during the second and third trimesters of pregnancy and postpartum. Plasma concentrations of amprenavir and ritonavir were measured using high-performance liquid chromatography. The target amprenavir area under the concentration-versus-time curve (AUC) was higher than the 10th percentile (27.7 μg · h/ml) of the median area under the curve for ritonavir-boosted fosamprenavir in adults receiving twice-daily fosamprenavir-ritonavir at 700 mg/100 mg. Twenty-nine women were included in the analysis. The amprenavir AUC from time zero to 12 h (AUC0–12) was lower (geometric mean ratio [GMR], 0.60 [confidence interval {CI}, 0.49 to 0.72] [P < 0.001]) while its apparent oral clearance was higher (GMR, 1.68 [CI, 1.38 to 2.03] [P < 0.001]) in the third trimester than postpartum. Similarly, the ritonavir AUC0–12 was lower in the second (GMR, 0.51 [CI, 0.28 to 0.91] [P = 0.09]) and third (GMR, 0.72 [CI, 0.55 to 0.95] [P = 0.005]) trimesters than postpartum, while its apparent oral clearance was higher in the second (GMR, 1.98 [CI, 1.10 to 3.56] [P = 0.06]) and third (GMR, 1.38 [CI, 1.05 to 1.82] [P = 0.009]) trimesters than postpartum. The amprenavir area under the curve exceeded the target for 6/8 (75%) women in the 2nd trimester, 18/28 (64%) in the 3rd trimester, and 19/22 (86.4%) postpartum, and the trough concentrations (Cmin) of amprenavir were 4- to 16-fold above the mean amprenavir-protein-adjusted 50% inhibitory concentration (IC50) of 0.146 μg/ml. Although amprenavir plasma concentrations in women receiving ritonavir-boosted fosamprenavir were lower during pregnancy than postpartum, the reduced amprenavir concentrations were still above the exposures needed for viral suppression.

Population Pharmacokinetic Analysis of the MDM2 Inhibitor KRT-232 (formerly AMG 232) in Subjects with Advanced Solid Tumors, Multiple Myeloma or Acute Myeloid Leukemia

Introduction KRT-232 is a potent and selective, targeted small molecule inhibitor of human mouse double minute 2 (MDM2) homolog interactions with tumor protein 53 (p53). MDM2 prevents p53 activation and reduces p53-mediated transcription and cell cycle control. KRT-232 is under development by Kartos Therapeutics for treatment of myelofibrosis, polycythemia vera, acute myeloid leukemia (AML) and Merkel cell carcinoma (see NCT03662126, NCT03669965, NCT03787602). Study 20120106 was a 2-part Phase 1 dose-exploration/dose-expansion study of KRT-232 in patients with advanced solid tumors or multiple myeloma (Gluck et al. Invest New Drugs in press; NCT01723020). Study 20120234 was a Phase 1b study evaluating KRT-232 alone and combined with trametinib, in patients with relapsed/refractory AML (Erba et al. Blood Adv 2019; NCT02016729). This population PK analysis quantified the KRT-232 PK time-course and variability, and the contribution of subject covariates to PK variability, using data from Amgen studies 20120106 and 20120234. Methods Study 20120106: Subjects received KRT-232 doses of 15 mg (n=3), 30 mg (n=3), 60 mg (n=4), 120 mg (n=7), 240 mg (n=76), 300 mg (n=4), 360 mg (n=4) and 480 mg (n=6). Doses were administered once daily (QD) for 7 days in 21-day cycles. PK sampling occurred on Cycle 1 days 1 and 7, at nominal sampling times pre-dose and 1, 3, 5, 7, and 24 h post-dose, and 72 h after the day 7 dose. Study 20120234: Subjects received KRT-232 doses of 60 mg (n=14; n=10 co-administered with 2 mg trametinib once daily, n=4 as single agent), 180 mg (n=5), 240 mg (n=3), and 360 mg (n=10). KRT-232 was administered QD for 7 days in 14-day cycles. PK sampling occurred on days 1 and 7, at nominal sampling times pre-dose and 1, 2, 4, 6, and 24 h post-dose, and 72 h after the day 7 dose. Population PK modeling was conducted using the first-order conditional estimation (FOCE-I) method in NONMEM® 7.3. Model covariates were selected using a forward addition and backward elimination method, based on significance levels of p<0.05 and p<0.01, respectively. Tested covariates included age, sex, weight, race, ethnicity, creatinine clearance, total bilirubin, AST, ALT, albumin, tumor type, disease stage, ECOG performance status, and the presence/absence of trametinib. Model quality was checked by inspection of model parameters and their confidence intervals, and standard residual-based and simulation-based diagnostics. Results KRT-232 plasma concentrations from 141 subjects with 1783 samples could be described by a two-compartment model with first-order absorption. Apparent oral clearance (CL/F) of KRT-232 was estimated to be 24.9 L/h (CV 61.5%) in subjects with solid tumors. The apparent oral central volume (Vc/F) and peripheral volume (Vp/F) were 62.9 L and 333 L, respectively. The terminal half-life was 17.1 hr. The prediction-corrected visual predictive check in Figure A suggested that the median, 5th and 95th percentiles of the measured plasma KRT-232 concentrations aligned with modeled concentrations for 24 h post-dose; the modeled variability was larger than the measured variability at 72 h post-dose. Residual diagnostics confirmed an adequate model fit. Apparent oral clearance did not change with dose over the studied dose range of 15-480 mg QD, indicating AUC increases were dose-proportional (Figure B). Relative to solid tumor subjects, AML subjects had 61.6% greater steady-state AUC (Figure C). A subject with decreased albumin at the 5th percentile (30 g/L) was modeled to have a 47.7% increase in AUC and an 87.2% increase in Cmin at steady state, relative to a typical subject with a median albumin level of 39 g/L. Trametinib and multiple myeloma model covariates had confidence intervals overlapping the line of unity. Covariates weight, sex, age, race and ethnicity did not affect CL/F or Vc/F. No effects of renal parameters, hepatic parameters, or ECOG performance status on CL/F were detected. Conclusion A two-compartment linear PK model with first-order absorption adequately described KRT-232 PK. Apparent oral clearance did not change with dose, indicating AUC increases were dose-proportional. AML subjects and subjects with decreased albumin had greater steady-state AUC values relative to subjects with solid tumors and normal albumin levels, although the magnitude of these effects were less than 2-fold. Disclosures Ma: Certara Strategic Consulting: Consultancy, Employment. Wada:Certara Strategic Consulting: Consultancy, Employment. Allard:Certara Strategic Consulting: Consultancy, Employment. Slatter:Kartos Therapeutics: Employment, Equity Ownership. OffLabel Disclosure: KRT-232 (formerly AMG 232) is an investigational small molecule MDM2 inhibitor.

Pharmacokinetics of the First-Line Antituberculosis Drugs in Ghanaian Children with Tuberculosis with or without HIV Coinfection

ABSTRACT Although human immunodeficiency virus (HIV) coinfection is the most important risk factor for a poor antituberculosis (anti-TB) treatment response, its effect on the pharmacokinetics of the first-line drugs in children is understudied. This study examined the pharmacokinetics of the four first-line anti-TB drugs in children with TB with and without HIV coinfection. Ghanaian children with TB on isoniazid, rifampin, pyrazinamide, and ethambutol for at least 4 weeks had blood samples collected predose and at 1, 2, 4, and 8 hours postdose. Drug concentrations were determined by validated liquid chromatography-mass spectrometry methods and pharmacokinetic parameters calculated using noncompartmental analysis. The area under the concentration-time curve from 0 to 8 h (AUC0–8), maximum concentration (C max), and apparent oral clearance divided by bioavailability (CL/F) for each drug were compared between children with and without HIV coinfection. Of 113 participants, 59 (52.2%) had HIV coinfection. The baseline characteristics were similar except that the coinfected patients were more likely to have lower weight-for-age and height-for-age Z scores (P < 0.05). Rifampin, pyrazinamide, and ethambutol median body weight-normalized CL/F values were significantly higher, whereas the plasma AUC0–8 values were lower, in the coinfected children than in those with TB alone. In the multivariate analysis, drug dose and HIV coinfection jointly influenced the apparent oral clearance and AUC0–8 for rifampin, pyrazinamide, and ethambutol. Isoniazid pharmacokinetics were not different by HIV coinfection status. HIV coinfection was associated with lower plasma exposure of three of the four first-line anti-TB drugs in children. Whether TB/HIV-coinfected children need higher dosages of rifampin, pyrazinamide, and ethambutol requires further investigation. (This study has been registered at ClinicalTrials.gov under identifier NCT01687504.)

Population Pharmacokinetic Modeling To Estimate the Contributions of Genetic and Nongenetic Factors to Efavirenz Disposition

ABSTRACT Efavirenz pharmacokinetics is characterized by large between-subject variability, which determines both therapeutic response and adverse effects. Some of the variability in efavirenz pharmacokinetics has been attributed to genetic variability in cytochrome P450 genes that alter efavirenz metabolism, such as CYP2B6 and CYP2A6. While the effects of additional patient factors have been studied, such as sex, weight, and body mass index, the extent to which they contribute to variability in efavirenz exposure is inconsistently reported. The aim of this analysis was to develop a pharmacometric model to quantify the contribution of genetic and nongenetic factors to efavirenz pharmacokinetics. A population-based pharmacokinetic model was developed using 1,132 plasma efavirenz concentrations obtained from 73 HIV-seronegative volunteers administered a single oral dose of 600 mg efavirenz. A two-compartment structural model with absorption occurring by zero- and first-order processes described the data. Allometric scaling adequately described the relationship between fat-free mass and apparent oral clearance, as well as fat mass and apparent peripheral volume of distribution. Inclusion of fat-free mass and fat mass in the model mechanistically accounted for correlation between these disposition parameters and sex, weight, and body mass index. Apparent oral clearance of efavirenz was reduced by 25% and 51% in subjects predicted to have intermediate and slow CYP2B6 metabolizer status, respectively. The final pharmacokinetic model accounting for fat-free mass, fat mass, and CYP2B6 metabolizer status was consistent with known mechanisms of efavirenz disposition, efavirenz physiochemical properties, and pharmacokinetic theory. (This study has been registered at ClinicalTrials.gov under identifier NCT00668395.)

Methadone Pharmacogenetics

Background Interindividual variability in methadone disposition remains unexplained, and methadone accidental overdose in pain therapy is a significant public health problem. Cytochrome P4502B6 (CYP2B6) is the principle determinant of clinical methadone elimination. The CYP2B6 gene is highly polymorphic, with several variant alleles. CYP2B6.6, the protein encoded by the CYP2B6*6 polymorphism, deficiently catalyzes methadone metabolism in vitro. This investigation determined the influence of CYP2B6*6, and other allelic variants encountered, on methadone concentrations, clearance, and metabolism. Methods Healthy volunteers in genotype cohorts CYP2B6*1/*1 (n = 21), CYP2B6*1/*6 (n = 20), and CYP2B6*6/*6 (n = 17), and also CYP2B6*1/*4 (n = 1), CYP2B6*4/*6 (n = 3), and CYP2B6*5/*5 (n = 2) subjects, received single doses of IV and oral methadone. Plasma and urine methadone and metabolite concentrations were determined by tandem mass spectrometry. Results Average S-methadone apparent oral clearance was 35 and 45% lower in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively, compared with CYP2B6*1/*1. R-methadone apparent oral clearance was 25 and 35% lower in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively, compared with CYP2B6*1/*1. R- and S-methadone apparent oral clearance was threefold and fourfold greater in CYP2B6*4 carriers. IV and oral R- and S-methadone metabolism was significantly lower in CYP2B6*6 carriers compared with that of CYP2B6*1 homozygotes and greater in CYP2B6*4 carriers. Methadone metabolism and clearance were lower in African Americans in part because of the CYP2B6*6 genetic polymorphism. Conclusions CYP2B6 polymorphisms influence methadone plasma concentrations, because of altered methadone metabolism and thus clearance. Genetic influence is greater for oral than IV methadone and S- than R-methadone. CYP2B6 pharmacogenetics explains, in part, interindividual variability in methadone elimination. CYP2B6 genetic effects on methadone metabolism and clearance may identify subjects at risk for methadone toxicity and drug interactions.

Lack of Indinavir Effects on Methadone Disposition Despite Inhibition of Hepatic and Intestinal Cytochrome P4503A (CYP3A)

Background Methadone disposition and pharmacodynamics are highly susceptible to interactions with antiretroviral drugs. Methadone clearance and drug interactions have been attributed to cytochrome P4503A4 (CYP3A4), but actual mechanisms are unknown. Drug interactions can be clinically and mechanistically informative. This investigation assessed effects of the protease inhibitor indinavir on methadone pharmacokinetics and pharmacodynamics, hepatic and intestinal CYP3A4/5 activity (using alfentanil), and intestinal transporter activity (using fexofenadine). Methods Twelve healthy volunteers underwent a sequential crossover. On three consecutive days they received oral alfentanil plus fexofenadine, intravenous alfentanil, and intravenous plus oral (deuterium-labeled) methadone. This was repeated after 2 weeks of indinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were measured by miosis. Results Indinavir significantly inhibited hepatic and first-pass CYP3A activity. Intravenous alfentanil systemic clearance and hepatic extraction were reduced to 40-50% of control, apparent oral clearance to 30% of control, and intestinal extraction decreased by half, indicating 50% and 70% inhibition of hepatic and first-pass CYP3A activity. Indinavir increased fexofenadine area under the plasma concentration-time curve 3-fold, suggesting significant P-glycoprotein inhibition. Indinavir had no significant effects on methadone plasma concentrations, methadone N-demethylation, systemic or apparent oral clearance, renal clearance, hepatic extraction or clearance, or bioavailability. Methadone plasma concentration-effect relationships were unaffected by indinavir. Conclusions Despite significant inhibition of hepatic and intestinal CYP3A activity, indinavir had no effect on methadone N-demethylation and clearance, suggesting little or no role for CYP3A in clinical disposition of single-dose methadone. Inhibition of gastrointestinal transporter activity had no influence of methadone bioavailability.