Population Pharmacokinetic Analysis of Fevipiprant in Healthy Subjects and Asthma Patients using a Tukey’s g-and-h Distribution

Abstract Aim The objective of this analysis was to characterize the population pharmacokinetics (PK) of fevipiprant in asthma patients and to evaluate the effect of baseline covariates on the PK of fevipiprant. Methods PK data from 1281 healthy subjects or asthma patients were available after single or once daily dosing of fevipiprant. Population PK analysis was conducted to describe fevipiprant plasma concentration data using a non-linear mixed effect modeling approach. Results Fevipiprant PK was described by a two-compartment model with first-order absorption and first-order elimination. Exploration of fevipiprant PK in the population from the phase III studies revealed an over-dispersed and skewed distribution. This unusual distribution was described using Tukey’s g-and-h distribution (TGH) on the between-subject variability of apparent clearance (CL/F). The model identified a significant impact of disease status on CL/F, with the value in healthy subjects being 62% higher than that in asthma patients. Bodyweight, age and renal function showed statistically significant impact on fevipiprant clearance; however, compared with a typical asthma patient, the simulated difference in steady-state exposure was at most 16%. Conclusion Fevipiprant PK was described by a two-compartment model with first-order absorption and first-order elimination. The TGH distribution was appropriate to describe the over-dispersed and skewed PK data as observed in the current studies. Asthma patients had approximately 37% higher exposure than healthy subjects did. Other covariates changed exposure by at most 16%.

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Population Pharmacokinetic Analysis of Voriconazole and Anidulafungin in Adult Patients with Invasive Aspergillosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02808-13 ◽

2014 ◽

Vol 58 (8) ◽

pp. 4718-4726 ◽

Cited By ~ 28

Author(s):

Ping Liu ◽

Diane R. Mould

Keyword(s):

Invasive Aspergillosis ◽

Area Under The Curve ◽

Compartment Model ◽

Population Pharmacokinetic Analysis ◽

Institutional Review Boards ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

First Order ◽

Two Compartment Model

ABSTRACTTo assess the pharmacokinetics (PK) of voriconazole and anidulafungin in patients with invasive aspergillosis (IA) in comparison with other populations, sparse PK data were obtained for 305 adults from a prospective phase 3 study comparing voriconazole and anidulafungin in combination versus voriconazole monotherapy (voriconazole, 6 mg/kg intravenously [IV] every 12 h [q12h] for 24 h followed by 4 mg/kg IV q12h, switched to 300 mg orally q12h as appropriate; with placebo or anidulafungin IV, a 200-mg loading dose followed by 100 mg q24h). Voriconazole PK was described by a two-compartment model with first-order absorption and mixed linear and time-dependent nonlinear (Michaelis-Menten) elimination; anidulafungin PK was described by a two-compartment model with first-order elimination. For voriconazole, the normal inverse Wishart prior approach was implemented to stabilize the model. Compared to previous models, no new covariates were identified for voriconazole or anidulafungin. PK parameter estimates of voriconazole and anidulafungin are in agreement with those reported previously except for voriconazole clearance (the nonlinear clearance component became minimal). At a 4-mg/kg IV dose, voriconazole exposure tended to increase slightly as age, weight, or body mass index increased, but the difference was not considered clinically relevant. Estimated voriconazole exposures in IA patients at 4 mg/kg IV were higher than those reported for healthy adults (e.g., the average area under the curve over a 12-hour dosing interval [AUC0–12] at steady state was 46% higher); while it is not definitive, age and concomitant medications may impact this difference. Estimated anidulafungin exposures in IA patients were comparable to those reported for the general patient population. This study was approved by the appropriate institutional review boards or ethics committees and registered on ClinicalTrials.gov (NCT00531479).

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Population Pharmacokinetic Model Linking Plasma and Peripheral Blood Mononuclear Cell Concentrations of Efavirenz and Its Metabolite, 8-Hydroxy-Efavirenz, in HIV Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00207-17 ◽

2017 ◽

Vol 61 (8) ◽

Cited By ~ 4

Author(s):

Abiy Habtewold ◽

Eleni Aklillu ◽

Eyasu Makonnen ◽

Getnet Yimer ◽

Leif Bertilsson ◽

...

Keyword(s):

Peripheral Blood ◽

Mononuclear Cells ◽

Compartment Model ◽

Central Compartment ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Concentration Data ◽

Peripheral Blood Mononuclear ◽

First Order ◽

Two Compartment Model

ABSTRACT The objectives of this study were to characterize the population pharmacokinetics (PK) of efavirenz (EFV) and 8-hydroxy-efavirenz (8OHEFV) in plasma and peripheral blood mononuclear cells (PBMCs) and to explore covariates affecting the PK parameters. Fifty-one patients had steady-state 0-to-24-h concentrations of EFV and 8OHEFV in plasma with corresponding concentrations in PBMCs, while 261 patients had one or two sparse concentrations at 16 ± 1 h postdose at weeks 4 and/or 16. The pharmacogenetic markers CYP2B6*6, CYP3A5*3, CYP3A5*6, UGT2B7*2, ABCB1 (3435C→T, 3842A→G), OATP1B1*1B, and OATP1B1*5, the presence of a rifampin-based antituberculosis (anti-TB) regimen, baseline body weight and organ function values, and demographic factors were explored as covariates. EFV concentration data were well described by a two-compartment model with first-order absorption (Ka ) and absorption lag time (A lag) (Ka = 0.2 h−1; A lag = 0.83 h; central compartment clearance [CLc/F] for CYP2B6*1/*1 = 18 liters/h, for CYP2B6*1/*6 = 14 liters/h, and for CYP2B6*6/*6 = 8.6 liters/h) and PBMCs as a peripheral compartment. EFV transfer from plasma to PBMCs was first order (CLp/F = 32 liters/h), followed by capacity-limited return (V max = 4,400 ng/ml/h; Km = 710 ng/ml). Similarly, 8OHEFV displayed a first-order elimination and distribution to PBMCs, with a capacity-limited return to plasma. No covariate relationships resulted in a significant explanation of interindividual variability (IIV) on the estimated PK parameters of EFV and 8OHEFV, except for CYP2B6*6 genotypes, which were consistent with prior evidence. Both EFV and 8OHEFV accumulated to higher concentrations in PBMCs than in plasma and were well described by first-order input and Michaelis-Menten kinetics removal from PBMCs. CYP2B6*6 genotype polymorphisms were associated with decreased EFV and 8OHEFV clearance.

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Population pharmacokinetics of the rilpivirine long-acting formulation after intramuscular dosing in healthy subjects and people living with HIV

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkab338 ◽

2021 ◽

Author(s):

M Neyens ◽

H M Crauwels ◽

J J Perez-Ruixo ◽

S Rossenu

Keyword(s):

Population Pharmacokinetics ◽

Healthy Subjects ◽

Phase Iii ◽

Intramuscular Administration ◽

Population Pharmacokinetic ◽

People Living With Hiv ◽

Concentration Data ◽

Flip Flop ◽

Long Acting ◽

Living With Hiv

Abstract Objectives To characterize the population pharmacokinetics of the rilpivirine long-acting (LA) formulation after intramuscular administration. Methods Rich and sparse rilpivirine plasma concentration data were obtained from seven clinical studies. In total, 18 261 rilpivirine samples were collected from 986 subjects (131 healthy subjects from Phase I studies and 855 people living with HIV from Phase IIb/III studies). Doses ranged from 300 to 1200 mg, as single-dose or multiple-dose regimens (every 4 or 8 weeks). In Phase III studies, an initiation injection of 900 mg followed by continuation injections of 600 mg every 4 weeks was used. Non-linear mixed-effects modelling was performed using NONMEM® software. Results A one-compartment model with linear elimination and two parallel absorption pathways (fast and slow) with sequential zero-first-order processes adequately captured rilpivirine flip-flop pharmacokinetics after intramuscular administration of the LA formulation. The estimated apparent elimination half-life of rilpivirine LA was 200 days. None of the evaluated covariates (age, body weight, BMI, sex, race, health status and needle length) had a clinically relevant impact on rilpivirine pharmacokinetics. Conclusions The population pharmacokinetic model suitably describes the time course and associated variability of rilpivirine plasma concentrations after rilpivirine LA intramuscular administration. The monthly regimen consists of an oral lead-in period (rilpivirine 25 mg tablets once daily for 4 weeks), followed by an initiation injection of 900 mg rilpivirine LA, then 600 mg rilpivirine LA continuation injections monthly. The absence of a clinically relevant effect of covariates on rilpivirine pharmacokinetics suggests that rilpivirine LA dose adjustments for specific subgroups are not warranted.

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Application of Population Pharmacokinetic Analysis to Characterize CYP2C19 Mediated Metabolic Mechanism of Voriconazole and Support Dose Optimization

Frontiers in Pharmacology ◽

10.3389/fphar.2021.730826 ◽

2022 ◽

Vol 12 ◽

Author(s):

SiChan Li ◽

SanLan Wu ◽

WeiJing Gong ◽

Peng Cao ◽

Xin Chen ◽

...

Keyword(s):

Maintenance Dose ◽

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Compartment Model ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Immunocompromised Patients ◽

First Order ◽

Dosing Regimens

Purpose: The aims of this study were to establish a joint population pharmacokinetic model for voriconazole and its N-oxide metabolite in immunocompromised patients, to determine the extent to which the CYP2C19 genetic polymorphisms influenced the pharmacokinetic parameters, and to evaluate and optimize the dosing regimens using a simulating approach.Methods: A population pharmacokinetic analysis was conducted using the Phoenix NLME software based on 427 plasma concentrations from 78 patients receiving multiple oral doses of voriconazole (200 mg twice daily). The final model was assessed by goodness of fit plots, non-parametric bootstrap method, and visual predictive check. Monte Carlo simulations were carried out to evaluate and optimize the dosing regimens.Results: A one-compartment model with first-order absorption and mixed linear and concentration-dependent-nonlinear elimination fitted well to concentration-time profile of voriconazole, while one-compartment model with first-order elimination well described the disposition of voriconazole N-oxide. Covariate analysis indicated that voriconazole pharmacokinetics was substantially influenced by the CYP2C19 genetic variations. Simulations showed that the recommended maintenance dose regimen would lead to subtherapeutic levels in patients with different CYP2C19 genotypes, and elevated daily doses of voriconazole might be required to attain the therapeutic range.Conclusions: The joint population pharmacokinetic model successfully characterized the pharmacokinetics of voriconazole and its N-oxide metabolite in immunocompromised patients. The proposed maintenance dose regimens could provide a rationale for dosage individualization to improve clinical outcomes and minimize drug-related toxicities.

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Higher Doses of Rituximab May Be Required for Patients with CLL as Compared to NHL Based On Population Pharmacokinetic (PK) Modeling.

Blood ◽

10.1182/blood.v114.22.1742.1742 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1742-1742 ◽

Cited By ~ 1

Author(s):

Jing Li ◽

Jianguo Zhi ◽

Michael K. Wenger ◽

Nancy Valente ◽

Jennifer Visich

Keyword(s):

Steady State ◽

Dose Regimen ◽

Compartment Model ◽

Rate Of Change ◽

Phase Iii ◽

Time Varying ◽

Malignant Cells ◽

Concentration Data ◽

Two Compartment Model ◽

Population Pk

Abstract Abstract 1742 Poster Board I-768 Introduction In the randomized Phase III study REACH, the combination of rituximab (R) (375 mg/m2 cycle 1, 500 mg/m2 cycles 2-6) and fludarabine (F) (25mg/m2 X 6 cycles) and cyclophosphamide (C) (250 mg/m2 X6 cycles) was shown to improve clinical response and prolong PFS in patients with relapsed/refractory Chronic Lymphocytic Leukemia (CLL) compared with F and C alone. The use of 500 mg/m2 as the dose of R in R-FC was guided by previous published data in CLL patients treated with R monotherapy demonstrating a probable dose-response relationship of a higher response rate at the higher dose levels (O'Brien JCO 2001, Byrd JCO 2001) and also by the data of high number of circulating malignant cells in CLL population (characteristic of CLL) which indicated that R might exhibit a higher clearance rate in CLL compared to observed clearance rates in NHL. Prior to the REACH study, the pharmacokinetics (PK) of R have not been thoroughly studied in the CLL population. As sub-study in REACH trial, a complete PK analysis of R was performed in CLL patients using a population PK analysis. This approach allowed not only the characterization of R PK in CLL patients, but also allowed for an opportunity to perform comparison of the PK differences between indications (CLL and NHL) and provided data-driven validation for the need of high R in CLL patients. Patients and Methods The PK of R were described with plasma concentrations from 21 CLL patients who received R-FC, using nonlinear mixed-effects modeling (NONMEM VI) software. A two-compartment model with time-varying clearance was validated using a bootstrap and visual predictive check method. The concentration vs. time profiles after given different dosages of R in NHL and CLL patients were predicted using the final models based on the observed data. Results R concentration data in CLL patients were well described by a two-compartment model with time-varying clearance, which has been used to describe R concentration data in NHL. Total clearance is comprised of two terms, a non-specific clearance pathway (CL1), which remains unchanged throughout treatment, and a specific clearance pathway (CL2) that decreases following a first-order decay rate from its initial value following the first infusion. The term Kdes represents the actual rate of change from the specific clearance (mediated by CD20) to the non-specific clearance (mediated by IgG1). The typical population estimates of R nonspecific clearance (CL1), and central compartment volume of distribution (V1) are similar between CLL and NHL (171 vs. 138 mL/day; 2310 vs. 2710 mL, respectively). However, the specific clearance (CL2) in CLL was much faster than that in NHL (1280 vs. 577 mL/day), and the rate of change (Kdes) from the specific clearance (mediated by CD20) to the non-specific clearance (mediated by IgG1) is two times lower for CLL patients compared to NHL patients (0.024 vs. 0.046 /day) and this suggests that it takes longer time for receptor saturation for CLL patients compared to NHL patients. The results of the simulation exercise showed that in the early cycles of the R-FC regimen, trough concentrations (Ctrough) and drug exposure (AUC) in CLL patients given 500 mg/m2 would be lower than those for NHL patients given 375 mg/m2 dose regimen. By the final cycles, the Ctrough and AUC of R are similar in NHL given 375 mg/m2 and CLL given 500 mg/m2. Conclusions Retrospective population PK analysis of R in CLL patients using non linear mixed effect modeling confirmed an increased R clearance during the early cycle of treatment as compared to NHL patients. This increased clearance is potentially due to a higher number of malignant cells in circulation for CLL patients, thus a larger dominance of the faster receptor-mediated clearance component in these patients, which overcome the lower CD20 density in CLL. The dose regimen of 500mg/m2 in CLL patients allows for reaching steady state AUC which is similar to the steady state AUC achieved with doses of 375mg/m2 given in NHL patients. Disclosures Li: Genentech: Employment. Zhi:Hoffmann-La Roche Inc.: Employment. Wenger:F. Hoffmann-La Roche Ltd: Employment. Valente:Genentech: Employment, Equity Ownership. Visich:Genentech: Employment.

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Development of a population pharmacokinetic (PPK) model of intravenous (IV) trastuzumab in patients with a variety of solid tumors to support dosing and treatment recommendations.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.2525 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 2525-2525 ◽

Cited By ~ 1

Author(s):

Whitney Paige Kirschbrown ◽

Angelica Linnea Quartino ◽

Hanbin Li ◽

Ranvir Mangat ◽

D Russell Wada ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast ◽

Compartment Model ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Tumor Type ◽

Concentration Data ◽

Two Compartment Model ◽

Linear And Nonlinear ◽

The Impact

2525 Background: The aim of this analysis was to develop a PPK model for IV trastuzumab (Herceptin), to assess the impact of patient covariates on PK, and perform simulations to support dosing recommendations. Methods: Serum trastuzumab concentration data (26,040 samples) from 1582 patients with metastatic breast cancer (MBC), early breast cancer (EBC), advanced gastric cancer (AGC) or other tumor types, and 6 healthy volunteers in 18 Phase I, II, and III trials were analyzed using nonlinear mixed-effects modeling (NONMEM). Monte Carlo simulations were performed using the NONMEM PK parameter estimates (with variability) to inform dosing recommendations. Results: A two-compartment model with parallel linear and nonlinear elimination best described the data. Significant covariates (P < 0.001) influencing linear CL were baseline weight, SGOT, albumin, primary tumor type, and presence of liver metastases. MBC had similar PK parameters as EBC, with lower distributions of Cmin,ss in MBC explained by covariates. The higher linear CL in AGC patients resulted in a 30.5% lower Cmin,ss. Simulations for drug washout indicated that 95% of patients with breast cancer (BC) reach trastuzumab concentrations < 1 µg/mL (~97% washout) at ≤7 months. Simulations also indicated that a missed dose of trastuzumab in BC or AGC patients of ≤1 week did not result in a long PK under-exposure (i.e. the trastuzumab concentration is within 15% of Cmin,ss by 3 weeks) but a missed dose of > 1 week took approximately 6 weeks to get back within the steady-state exposure range. Conclusions: Trastuzumab PK was well described by a two-compartment model with parallel linear and nonlinear eliminationacross cancer types, disease status, and regimens. No dose adjustment is required based on any of the identified patient covariates (e.g. weight, tumor type). Simulations using the PPK model informed the prescribing information for Herceptin; trastuzumab has a 7-month serum washout period during which patients should avoid an anthracycline-based therapy, pregnancy, or breastfeeding. A re-loading dose is required if a maintenance dose is missed by > 1 week to maintain serum concentrations.

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Population Pharmacokinetic Analysis of Isoniazid, Acetylisoniazid, and Isonicotinic Acid in Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01244-15 ◽

2015 ◽

Vol 59 (11) ◽

pp. 6791-6799 ◽

Cited By ~ 16

Author(s):

Kok-Yong Seng ◽

Kim-Hor Hee ◽

Gaik-Hong Soon ◽

Nicholas Chew ◽

Saye H. Khoo ◽

...

Keyword(s):

Isonicotinic Acid ◽

Compartment Model ◽

Hepatic Function ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Mixed Effects Modeling ◽

Two Compartment Model

ABSTRACTIn this study, we aimed to quantify the effects of theN-acetyltransferase 2 (NAT2) phenotype on isoniazid (INH) metabolismin vivoand identify other sources of pharmacokinetic variability following single-dose administration in healthy Asian adults. The concentrations of INH and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) in plasma were evaluated in 33 healthy Asians who were also given efavirenz and rifampin. The pharmacokinetics of INH, AcINH, and INA were analyzed using nonlinear mixed-effects modeling (NONMEM) to estimate the population pharmacokinetic parameters and evaluate the relationships between the parameters and the elimination status (fast, intermediate, and slow acetylators), demographic status, and measures of renal and hepatic function. A two-compartment model with first-order absorption best described the INH pharmacokinetics. AcINH and INA data were best described by a two- and a one-compartment model, respectively, linked to the INH model. In the final model for INH, the derived metabolic phenotypes for NAT2 were identified as a significant covariate in the INH clearance, reducing its interindividual variability from 86% to 14%. The INH clearance in fast eliminators was 1.9- and 7.7-fold higher than in intermediate and slow eliminators, respectively (65 versus 35 and 8 liters/h). Creatinine clearance was confirmed as a significant covariate for AcINH clearance. Simulations suggested that the current dosing guidelines (200 mg for 30 to 45 kg and 300 mg for >45 kg) may be suboptimal (3 mg/liter ≤Cmax≤ 6 mg/liter) irrespective of the acetylator class. The analysis established a model that adequately characterizes INH, AcINH, and INA pharmacokinetics in healthy Asians. Our results refine the NAT2 phenotype-based predictions of the pharmacokinetics for INH.

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Population pharmacokinetic (PPK) analysis for 5-FU, tegafur (FT), gimeracil (CDHP), and oteracil potassium (Oxo) in the eight clinical studies of S-1 in Western patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.53 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 53-53 ◽

Cited By ~ 1

Author(s):

K. Yoshida ◽

K. Ikeda ◽

K. Yoshisue ◽

W. Rodriguez ◽

G. Bodoky ◽

...

Keyword(s):

Renal Function ◽

Model Simulation ◽

Visual Predictive Check ◽

Compartment Model ◽

Phase Iii ◽

Population Pharmacokinetic ◽

Extrinsic Factors ◽

Minimal Impact ◽

Two Compartment Model ◽

Number Of Patients

53 Background: This analysis was performed to establish the PPK model of S-1, and to identify the intrinsic or extrinsic factors that influence S-1 exposure in the Western patients with advanced solid tumor. Methods: PK data obtained in seven phase I and one phase III (FLAGS) studies were combined for PPK analysis. The total number of patients was 315, and the number of data points for FT, CDHP, 5-FU and Oxo were 2,860, 2,625, 2,492, and 2,484, respectively. The two-compartment model was used for FT, CDHP and Oxo, whereas for 5-FU, inhibitory effect of CDHP on 5-FU clearance was incorporated into a two-compartment model to describe its non-linear PK. The final models were validated by visual predictive check and bootstrapping. Results: The individual fit and the stability of four models were acceptable. The predicted daily AUCs (at steady state) were calculated to evaluate the effect of covariates. The daily AUC of 5-FU strongly correlated with oral clearance (CL/F) of CDHP, but not with that of FT. The ethnic difference in exposure to 5-FU was not apparent despite the significantly lower CL/F of FT observed in the Asian patients. Co-administration with food delayed the absorption of S-1 but exhibited no or limited effect on the AUC of FT, CDHP and 5-FU, whereas the bioavailability of Oxo decreased to approximately 30%. Renal function primarily influenced CDHP exposure and, in turn, 5-FU. The model simulation suggested that the S-1 dosages of 30, 25 and 20 mg/m2 BID could achieve similar daily AUC of 5-FU in the Western patients with normal renal function (CLcr>80 mL/min), mild (50-80 mL/min) and moderate (30-50 mL/min) renal impairment, respectively. Other factors such as age, gender, liver function, serum albumin, PS, gastric cancer, gastrectomy, combination with cisplatin and liver metastasis, had little or minimal impact on the daily AUC of 5-FU. Conclusions: This analysis suggests that the daily AUC of 5-FU after S-1 administration is primarily affected by the CDHP levels, and hence renal function remains the primary factor for 5-FU PK in patients. Other factors as well as CL/F of FT had little impact on 5-FU. [Table: see text]

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Population Pharmacokinetic Analysis of Isoniazid among Pulmonary Tuberculosis Patients from China

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01736-19 ◽

2020 ◽

Vol 64 (3) ◽

Author(s):

Wei Jing ◽

Zhaojing Zong ◽

Bohao Tang ◽

Jing Wang ◽

Tingting Zhang ◽

...

Keyword(s):

Compartment Model ◽

Population Pharmacokinetic Analysis ◽

Slow Acetylators ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Time Curve ◽

Tuberculosis Patients ◽

Two Compartment Model ◽

Acetylator Status ◽

Liquid Chromatography Tandem Mass

ABSTRACT The blood concentration of isoniazid (INH) is evidently affected by polymorphisms in N-acetyltransferase 2 (NAT2), an enzyme that is primarily responsible for the trimodal (i.e., fast, intermediate, and slow) INH elimination. The pharmacokinetic (PK) variability, driven largely by NAT2 activity, creates a challenge for the deployment of a uniform INH dosage in tuberculosis (TB) patients. Although acetylator-specific INH dosing has long been suggested, well-recognized dosages according to acetylator status remain elusive. In this study, 175 blood samples were collected from 89 pulmonary TB patients within 0.5 to 6 h after morning INH administration. According to their NAT2 genotypes, 32 (36.0%), 38 (42.7%), and 19 (21.3%) were fast, intermediate, and slow acetylators, respectively. The plasma INH concentration was detected by liquid chromatography-tandem mass spectrometry. Population pharmacokinetic (PPK) analysis was conducted using NONMEM and R software. A two-compartment model with first-order absorption and elimination well described the PK parameters of isoniazid. Body weight and acetylator status significantly affected the INH clearance rate. The dosage simulation targeting three indicators, including the well-recognized efficacy-safety indicator maximum concentration in serum (Cmax; 3 to 6 μg/ml), the reported area under the concentration-time curve from 0 h to infinity (AUC0–∞; ≥10.52 μg·h/ml), and the 2-h INH serum concentrations (≥2.19 μg/ml), was associated with the strongest early bactericidal activity. The optimal dosages targeting the different indicators varied from 700 to 900 mg/day, 500 to 600 mg/day, and 300 mg/day for the rapid, intermediate, and slow acetylators, respectively. Furthermore, a PPK model for isoniazid among Chinese tuberculosis patients was established for the first time and suggested doses of approximately 800 mg/day, 500 mg/day, and 300 mg/day for fast, intermediate, and slow acetylators, respectively, after a trade-off between efficacy and the occurrence of side effects.

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