Population pharmacokinetics of bedaquiline in patients with drug-resistant TB

OBJECTIVE: To develop a population pharmacokinetic (PK) model for bedaquiline (BDQ) to describe the concentration-time data from patients with multidrug-resistant TB (MDR-TB) in China.METHOD: A total of 306 PK observations from 69 patients were used in a non-linear, mixed-effects modelling (NONMEM) approach. BDQ PK can be adequately described by a three-compartment model with a transit absorption model. The impact of baseline covariates, including age, sex, height, weight, alanine aminotransferase (ALT), aspartate aminotransferase (AST), apolipoprotein (ALP), total bilirubin (TBIL), direct bilirubin (DBIL), creatinine (CR), potassium (K+), calcium (Ca++) and magnesium (Mg++) on the oral clearance (CL/F) of BDQ were investigated.RESULTS: In final population PK model, no significant covariates were found in the population PK model for BDQ. The population PK parameter estimate values for oral clearance (CL/F); CL/F between central compartment and peripheral compartment (Q1/F, Q2/F); peripheral volume of distribution (Vp1/F, VP2/F) were respectively 1.50 L/h (95% CI 1.07–1.93), 2.54 L/h (95% CI 1.67–3.41), 1,250 L (95% CI 616.9–1883.1), 2.00 L/h (95% CI 1.10–2.90) and 4,960 L (95% CI 1647.6–8272.4). Inter-individual variability on CL/F was 65.0%.CONCLUSION: This is the first study to establish a population PK model for BDQ in Chinese patients with MDR-TB. The final model adequately described the data and had good simulation characteristics. Despite some limitations, the final population PK model was stable with good accuracy of parameter estimation.

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.

Nevirapine pharmacokinetics in HIV-infected persons receiving rifapentine and isoniazid for TB prevention

Background The use of rifamycin antibiotics for TB prevention carries a risk of detrimental drug–drug interactions with concomitantly used ART. Objectives To evaluate the interaction of the antiretroviral drug nevirapine in combination with 4 weeks of daily rifapentine and isoniazid for TB prevention in people living with HIV. Methods Participants were individuals enrolled in the BRIEF-TB study receiving nevirapine and randomized to the rifapentine/isoniazid arm of the study. Participants provided sparse pharmacokinetic (PK) sampling at baseline and weeks 2 and 4 for trough nevirapine determination. Nevirapine apparent oral clearance (CL/F) was estimated and the geometric mean ratio (GMR) of CL/F prior to and during rifapentine/isoniazid was calculated. Results Seventy-eight participants had evaluable PK data: 61 (78%) female, 51 (65%) black non-Hispanic and median (range) age of 40 (13–66) years. Median (IQR) nevirapine trough concentrations were: week 0, 7322 (5266–9302) ng/mL; week 2, 5537 (3552–8462) ng/mL; and week 4, 5388 (3516–8243) ng/mL. Sixty out of 78 participants (77%) had nevirapine concentrations ≥3000 ng/mL at both week 2 and 4. Median (IQR) nevirapine CL/F values were: week 0 pre-rifapentine/isoniazid, 2.03 (1.58–2.58) L/h; and during rifapentine/isoniazid, 2.62 (1.81–3.42) L/h. The GMR (90% CI) for nevirapine CL/F was 1.30 (1.26–1.33). Conclusions The CL/F of nevirapine significantly increased with concomitant rifapentine/isoniazid. The decrease in nevirapine trough concentrations during rifapentine/isoniazid therapy suggests induction of nevirapine metabolism, consistent with known rifapentine effects. The magnitude of this drug–drug interaction suggests daily rifapentine/isoniazid for TB prevention should not be co-administered with nevirapine-containing ART.

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.

CARIOGENICITY OF VARIOUS FOOD PRODUCTS AND ITS ORAL CLEARANCE –A REVIEW ARTICLE

Dental caries is a disease, the onset of which is dependent on a combination of multiple factors like microorganisms, host i.e, susceptible teeth, diet: fer­mentable carbohydrate, and time. Re­search efforts have been made to under­stand the contribution of each component on the resulting dental caries. Prediction of a food's cariogenicity can be most usefully regarded as a relative assessment of the food's potential, among other foods, to give rise to caries, with other modifying factors held constant. Keywords: Cariogenicity, Dental caries, Diet

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 Pharmacokinetics of Ruxolitinib in Patients with aGVHD Who Had an Inadequate Response to Corticosteroids

Background: Jakafi® (ruxolitinib) is currently approved for the treatment of adult patients with intermediate- and high-risk myelofibrosis (MF) and for the treatment of adult patients with polycythemia vera (PV) who have had an inadequate response to or are intolerant to hydroxyurea. A prospective, open-label, single-cohort, Phase 2 study (REACH1) was conducted to evaluate the safety and efficacy of Jakafi® (ruxolitinib) in patients with acute graft versus host disease (aGVHD) who have had an inadequate response to corticosteroids. A population PK analysis was employed to characterize the PK of ruxolitinib in this patient population. Patients and Methods: REACH1, Study INCB 18424-251, and COMFORT-I are the 3 studies supporting the population PK of ruxolitinib; the first study is in participants with aGVHD who have had an inadequate response to corticosteroids, and the other 2 studies are in participants with MF. First, the final PK model for ruxolitinib in patients with MF was applied to the data in patients with MF and aGVHD. When significant biases were observed in this validation process, new population PK models were developed based on the pooled data. The accuracy and robustness of the final population PK model were assessed using a predictive check method. Results: An under-prediction bias was observed at the population level when existing PK model in MF was applied to pooled data in patients with MF and aGVHD. A new model was developed to account for the under prediction bias at the population level. The final population PK model for ruxolitinib was a 2 compartment disposition model with first order absorption, absorption lag time, and linear elimination. Body weight and gender were significant predictors of the volume of distribution of the central compartment and oral clearance, respectively. Patients with aGVHD showed lower oral clearance (66.7%) and slower rate of absorption (~28%) than that in patients with MF. The stage of liver involvement in GVHD and use of moderate or potent CYP3A4 inhibitors were identified as covariates for ruxolitinib CL. Conclusion: The population PK analysis supports the proposed dose regimen in patients with aGVHD who had an inadequate response to corticosteroids as well as dose recommendations for DDI and subjects with organ dysfunction. Disclosures Chen: Incyte Research Institute: Employment. Liu:Incyte Research Institute: Employment. Wang:Incyte Research Institute: Employment. Yeleswaram:Incyte Research Institute: Employment.

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.