Unexpectedly low drug exposures among Ugandan patients with TB and HIV receiving high-dose rifampicin.

We characterized the pharmacokinetics of standard- and high-dose rifampicin in Ugandan adults with tuberculosis and HIV taking dolutegravir- or efavirenz-based antiretroviral therapy. A liver model with saturable hepatic extraction adequately described the data, and the increase in exposure between high and standard doses was 4.7-fold. This was lower than what previous reports of dose-exposure nonlinearity would predict and was ascribed to 38% lower bioavailability of the rifampicin-only top-up formulation compared to the fixed-dose combination.

Pharmacokinetics of oral antimycobacterials and dosing guidance for Mycobacterium avium complex treatment in cystic fibrosis.

BACKGROUND: Treatment failure of Mycobacterium avium complex (MAC) pulmonary disease occurs in about 30% of people with cystic fibrosis (CF) and may be a result of abnormal drug concentrations. METHODS: Prospective, cross-over, single-dose PK study of 20 pancreatic insufficient individuals with CF and 10 healthy controls (HC). CF subjects received simultaneous doses of oral azithromycin, ethambutol, and rifampin in the fasting state and with food and pancreatic enzymes, separated by two weeks. HC received fasting doses only. A non-compartmental model was used to estimate PK parameters of drugs and metabolites. RESULTS: Azithromycin maximum concentration (Cmax ) was higher and rifampin Cmax was lower in fasting CF subjects compared to HC, while other PK measures, including those for ethambutol, were similar. Addition of food and enzymes did not improve the Cmax of the antimycobacterial drugs. Nineteen of 20 CF subjects had one or more abnormal Cmax z-scores in either the fasting or fed state (or both), when compared to HC. CONCLUSION: PK profiles of azithromycin and ethambutol were similar between CF and HC, except azithromycin Cmax was slightly higher in people with CF after a single dose. Rifampin PK parameters were altered in persons with CF. Addition of food and enzymes in CF subjects did not improve PK parameters. Standard dosing guidelines should be used as a starting point for people with CF initiating MAC therapy and therapeutic drug monitoring should be routinely performed to prevent the possibility of treatment failure due to abnormal drug concentrations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02372383 Prior abstract publication: 1. Martiniano S, Wagner B, Brennan L, Wempe M, Anderson P, Nick J, Sagel S. Pharmacokinetics of oral MAC antibiotics in cystic fibrosis. Am J Resp Crit Care Med A4842-A4842, 2017. 2. Martiniano SL, Wagner BD, Brennan L, Wempe MF, Anderson PL, Nick JA, Sagel SD. Pharmacokinetics of oral MAC antibiotics in cystic fibrosis. J Cyst Fibros 16: S52-53, 2017.

Neuropsychiatric toxicity and cycloserine concentrations during treatment for multidrug-resistant tuberculosis.

BACKGROUND: Cycloserine, or its structural analogue terizidone, has been associated with neuropsychiatric toxicity (psychosis, depression, and neuropathy). Prospective clinical data on the incidence of and risk factors for neuropsychiatric toxicity in TB patients treated with cycloserine are limited. METHODS: A prospective evaluation of neuropsychiatric toxicity was performed using validated screening tools in patients with multidrug-resistant tuberculosis treated with terizidone. Cox proportional hazard modelling was performed to explore the effects of clinical variables and measures of cycloserine pharmacokinetics in plasma. RESULTS: A total 144 participants were recruited: 86 were male and 58 were female; their median age was 35.7 years and 91 (63%) were HIV-infected. Fifty-five (38%) participants developed at least one neuropsychiatric event (30 cases per 100 person-months): 50 (35%) neuropathy, 14 (10%) depression, and 11 (8%) psychosis. Neuropathy was independently associated with cycloserine clearance ((adjusted hazard ratio 0.34 (aHR), P = 0.03)) and high-dose pyridoxine (200 mg vs 150 mg daily, aHR: 2.79, P = 0.01). CONCLUSIONS: A high incidence of early neuropsychiatric toxicity was observed in this cohort of patients treated with terizidone. Cycloserine clearance and higher doses of pyridoxine are associated with incident or worsening peripheral neuropathy.

Experimental Solubility, Thermodynamic/Computational Validations, and GastroPlus-Based In Silico Prediction for Subcutaneous Delivery of Rifampicin.

We focused to explore a suitable solvent for rifampicin (RIF) recommended for subcutaneous (sub-Q) delivery [ethylene glycol (EG), propylene glycol (PG), tween 20, polyethylene glycol-400 (PEG400), oleic acid (OA), N-methyl-2-pyrrolidone (NMP), cremophor-EL (CEL), ethyl oleate (EO), methanol, and glycerol] followed by computational validations and in-silico prediction using GastroPlus. The experimental solubility was conducted over temperature ranges T = 298.2-318.2 K) and fixed pressure (p = 0.1 MPa) followed by validation employing computational models (Apelblat, and van't Hoff). Moreover, the HSPiP solubility software provided the Hansen solubility parameters. At T = 318.2K, the estimated maximum solubility (in term of mole fraction) values of the drug were in order of NMP (11.9 × 10-2) ˃ methanol (6.8 × 10-2) ˃ PEG400 (4.8 × 10-2) ˃ tween 20 (3.4 × 10-2). The drug dissolution was endothermic process and entropy driven as evident from "apparent thermodynamic analysis". The activity coefficients confirmed facilitated RIF-NMP interactions for increased solubility among them. Eventually, GastroPlus predicted the impact of critical input parameters on major pharmacokinetics responses after sub-Q delivery as compared to oral delivery. Thus, NMP may be the best solvent for sub-Q delivery of RIF to treat skin tuberculosis (local and systemic) and cutaneous related disease at explored concentration.

Pharmacokinetics of rifampicin after repeated intra-tracheal administration of amorphous and crystalline powder formulations to Sprague Dawley rats.

Rifampicin is one of the key drugs used to treat tuberculosis and is currently used orally. The use of higher oral doses of rifampicin is desired for better therapeutic efficacy, but this is accompanied by increased risk of systemic toxicity thus limiting its recommended oral dose to 10 mg/kg per day. Inhaled delivery of rifampicin is a potential alternative mode of delivery, to achieve high drug concentrations in both the lung and potentially the systemic circulation. In addition, rifampicin exists either as amorphous or crystalline particles, which may show different pharmacokinetic behaviour. However, disposition behaviour of amorphous and crystalline rifampicin formulations after inhaled high-dose delivery is unknown. In this study, rifampicin pharmacokinetics after intra-tracheal administration of carrier-free, amorphous and crystalline powder formulations to Sprague Dawley rats were evaluated. The formulations were administered once daily for seven days by oral, intra-tracheal and oral plus intra-tracheal delivery, and the pharmacokinetics were studied on day 0 and day 6. Intra-tracheal administration of the amorphous formulation resulted in a higher area under the plasma concentration curve (AUC) compared to the crystalline formulation. For both formulations, the intra-tracheal delivery led to significantly higher AUC compared to the oral delivery at the same dose suggesting higher rifampicin bioavailability from the inhaled route. Increasing the intra-tracheal dose resulted in a more than dose proportional AUC suggesting non-linear pharmacokinetics of rifampicin from the inhaled route. Upon repeated administration for seven days, no significant decrease in the AUCs were observed suggesting the absence of rifampicin induced enzyme auto-induction in this study. The present study suggests an advantage of inhaled delivery of rifampicin in achieving higher drug bioavailability compared to the oral route.

Model-Informed Pediatric Dose Selection for Dapagliflozin by Incorporating Developmental Changes.

This analysis reports a quantitative modeling and simulation approach for oral dapagliflozin, a primarily uridine diphosphate-glucuronosyltransferase (UGT)-metabolized human sodium-glucose cotransporter 2 selective inhibitor. A mechanistic dapagliflozin physiologically based pharmacokinetic (PBPK) model was developed using in vitro metabolism and clinical pharmacokinetic (PK) data and verified for context of use (e.g., exposure predictions in pediatric subjects aged 1 month to 18 years). Dapagliflozin exposure is challenging to predict in pediatric populations owing to differences in UGT1A9 ontogeny maturation and paucity of clinical PK data in younger age groups. Based on the exposure-response relationship of dapagliflozin, twofold acceptance criteria were applied between model-predicted and observed drug exposures and PK parameters (area under the curve and maximum drug concentration) in various scenarios, including monotherapy in healthy adults (single/multiple dose), monotherapy in hepatically or renally impaired patients, and drug-drug interactions with UGT1A9 modulators, such as mefenamic acid and rifampin. The PBPK model captured the observed exposure within twofold of the observed monotherapy data in adults and adolescents and in special population. As a guide to determining dosing regimens in pediatric studies, the verified PBPK model, along with UGT enzyme ontogeny maturation understanding, was used for predictions of dapagliflozin monotherapy exposures in pediatric subjects aged 1 month to 18 years that best matched exposure in adult patients with a 10-mg single dose of dapagliflozin.

A population approach of rifampicin pharmacogenetics and pharmacokinetics in Mexican patients with tuberculosis.

The aim of this study was to develop a population pharmacokinetic model of rifampicin (RMP) in Mexican patients with tuberculosis (TB) to evaluate the influence of anthropometric and clinical covariates, as well as genotypic variants associated with MDR1 and OATP1B1 transporters. A prospective study approved by Research Ethics Committee was performed at Hospital Central in San Luis Potosí, Mexico. TB patients under DOTS scheme and who signed informed consent were consecutively included. Anthropometric and clinical information was retrieved from medical records. Single nucleotide polymorphisms in MDR1 (C3435T) and SLCO1B1 (A388G and T521C) genes were evaluated. RMP plasma concentrations and time data were assessed with NONMEM software. A total of 71 Mexican TB patients from 18 to 72 years old were included for RMP quantification from 0.3 to 12 h after dose; 329 and 97 plasma concentrations were available for model development and validation, respectively. Sequential process includes a typical lag time of 0.25 h prior to absorption start with a Ka of 1.24 h-1 and a zero-order absorption of 0.62 h to characterize the gradual increase in RMP plasma concentrations. Final model includes total body weight in volume of distribution (0.7 L/kg, CV = 26.8%) and a total clearance of 5.96 L/h (CV = 38.5%). Bioavailability was modified according to time under treatment and generic formulation administration. In conclusion, a population pharmacokinetic model was developed to describe the variability in RMP plasma concentrations in Mexican TB patients. Genetic variants evaluated did not showed significant influence on pharmacokinetic parameters. Final model will allow therapeutic drug monitoring at early stages.

Rifapentine Population Pharmacokinetics and Dosing Recommendations for Latent Tuberculosis Infection.

Rationale: Rifapentine has been investigated at various doses, frequencies, and dosing algorithms, but clarity on the optimal dosing approach is lacking.Objectives: To characterize rifapentine population pharmacokinetics, including autoinduction, and determine optimal dosing strategies for short-course rifapentine-based regimens for latent tuberculosis infection.Methods: Rifapentine pharmacokinetic studies were identified though a systematic review of literature. Individual plasma concentrations were pooled, and nonlinear mixed-effects modeling was performed. A subset of data was reserved for external validation. Simulations were performed under various dosing conditions, including current weight-based methods; and alternative methods driven by identified covariates.Measurements and Main Results: We identified nine clinical studies with a total of 863 participants with pharmacokinetic data (n = 4,301 plasma samples). Rifapentine population pharmacokinetics were described successfully with a one-compartment distribution model. Autoinduction of clearance was driven by rifapentine plasma concentrations. The maximum effect was a 72% increase in clearance and was reached after 21 days. Drug bioavailability decreased by 27% with HIV infection, decreased by 28% with fasting, and increased by 49% with a high-fat meal. Body weight was not a clinically relevant predictor of clearance. Pharmacokinetic simulations showed that current weight-based dosing leads to lower exposures in individuals with low weight, which can be overcome with flat dosing. In HIV-positive patients, 30% higher doses are required to match drug exposure in HIV-negative patients.Conclusions: Weight-based dosing of rifapentine should be removed from clinical guidelines, and higher doses for HIV-positive patients should be considered to provide equivalent efficacy.

Pharmacokinetics, SAfety/tolerability, and EFficacy of high-dose RIFampicin in tuberculosis-HIV co-infected patients on efavirenz- or dolutegravir-based antiretroviral therapy: study protocol for an open-label, phase II clinical trial (SAEFRIF).

BACKGROUND: Tuberculosis (TB) is a significant public health problem that causes substantial morbidity and mortality. Current first-line anti-TB chemotherapy, although very effective, has limitations including long-treatment duration with a possibility of non-adherence, drug interactions, and toxicities. Dose escalation of rifampicin, an important drug within the regimen, has been proposed as a potential route to higher treatment efficacy with shorter duration and some studies have suggested that dose escalation is safe; however, these have almost entirely been conducted among human immunodeficiency (HIV)-negative TB patients. TB-HIV co-infected patients on antiretroviral therapy (ART) are at increased risk of drug-drug interactions and drug-related toxicities. This study aims to determine the safety of higher doses of rifampicin and its effect on the pharmacokinetics of efavirenz (EFV) and dolutegravir (DTG) in TB-HIV co-infected patients. METHODS: This study is a randomized, open-label, phase IIb clinical trial among TB-HIV infected adult outpatients attending an HIV clinic in Kampala, Uganda. Patients newly diagnosed with TB will be randomized to either standard-dose or high-dose rifampicin (35 mg/kg) alongside standard TB treatment. ART-naïve patients will be randomly assigned to first-line ART regimens (DTG or EFV). Those who are already on ART (DTG or EFV) at enrollment will be continued on the same ART regimen but with dose adjustment of DTG to twice daily dosing. Participants will be followed every 2 weeks with assessment for toxicities at each visit and measurement of drug concentrations at week 6. At the end of intensive-phase therapy (8 weeks), all participants will be initiated on continuation-phase treatment using standard-dose rifampicin and isoniazid. DISCUSSION: This study should avail us with evidence about the effect of higher doses of rifampicin on the pharmacokinetics of EFV and DTG among TB-HIV co-infected patients. The trial should also help us to understand safety concerns of high-dose rifampicin among this vulnerable cohort. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03982277. Registered retrospectively on 11 June 2019.

Translational Model-Informed Approach for Selection of Tuberculosis Drug Combination Regimens in Early Clinical Development.

The development of optimal treatment regimens in tuberculosis (TB) remains challenging due to the need of combination therapy and possibility of pharmacodynamic (PD) interactions. Preclinical information about PD interactions needs to be used more optimally when designing early bactericidal activity (EBA) studies. In this work, we developed a translational approach which can allow for forward translation to predict efficacy of drug combination in EBA studies using the Multistate Tuberculosis Pharmacometric (MTP) and the General Pharmacodynamic Interaction (GPDI) models informed by in vitro static time-kill data. These models were linked with translational factors to account for differences between the in vitro system and humans. Our translational MTP-GPDI model approach was able to predict the EBA0-2 days , EBA0-5 days , and EBA0-14 days from different EBA studies of rifampicin and isoniazid in monotherapy and combination. Our translational model approach can contribute to an optimal dose selection of drug combinations in early TB clinical trials.

Antitubercular nanocarrier monotherapy: Study of In Vivo efficacy and pharmacokinetics for rifampicin.

Tuberculosis represents a major global health problem for which improved approaches are needed to shorten the course of treatment and to combat the emergence of resistant strains. The development of effective and safe nanobead-based interventions can be particularly relevant for increasing the concentrations of antitubercular agents within the infected site and reducing the concentrations in the general circulation, thereby avoiding off-target toxic effects. In this work, rifampicin, a first-line antitubercular agent, was encapsulated into biocompatible and biodegradable polyester-based nanoparticles. In a well-established BALB/c mouse model of pulmonary tuberculosis, the nanoparticles provided improved pharmacokinetics and pharmacodynamics. The nanoparticles were well tolerated and much more efficient than an equivalent amount of free rifampicin.

Pharmacokinetic Modeling, Simulation, and Development of a Limited Sampling Strategy of Cycloserine in Patients with Multidrug-/Extensively Drug-Resistant Tuberculosis.

BACKGROUND AND OBJECTIVE: Multidrug-resistant tuberculosis has much poorer treatment outcomes compared with drug-susceptible tuberculosis because second-line drugs for treating multidrug resistant tuberculosis are less effective and are frequently associated with side effects. Optimization of drug treatment is urgently needed. Cycloserine is a second-line tuberculosis drug with variable pharmacokinetics and thus variable exposure when programmatic doses are used. The objective of this study was to develop a population pharmacokinetic model of cycloserine to assess drug exposure and to develop a limited sampling strategy for cycloserine exposure monitoring. MATERIAL AND METHODS: Patients with multidrug-/extensively drug-resistant tuberculosis who were treated for > 7 days with cycloserine were eligible for inclusion. Patients received cycloserine 500 mg (body weight ≤ 50 kg) or 750 mg (body weight > 50 kg) once daily. MW/Pharm 3.83 (Mediware, Groningen, The Netherlands) was used to parameterize the population pharmacokinetic model. The model was compared with pharmacokinetic values from the literature and evaluated with a bootstrap analysis, Monte Carlo simulation, and an external dataset. Monte Carlo simulations were used to develop a limited sampling strategy. RESULTS: Cycloserine plasma concentration vs time curves were obtained from 15 hospitalized patients (nine male, six female, median age 35 years). Mean dose/kg body weight was 11.5 mg/kg (standard deviation 2.04 mg/kg). Median area under the concentration-time curve over 24 h (AUC0-24 h) of cycloserine was 888 h mg/L (interquartile range 728-1252 h mg/L) and median maximum concentration of cycloserine was 23.31 mg/L (interquartile range 20.14-33.30 mg/L). The final population pharmacokinetic model consisted of the following pharmacokinetic parameters [mean (standard deviation)]: absorption constant Ka_po of 0.39 (0.31) h-1, distribution over the central compartment (Vd) of 0.54 (0.26) L/kg LBM, renal clearance as fraction of the estimated glomerular filtration rate of 0.092 (0.038), and metabolic clearance of 1.05 (0.75) L/h. The population pharmacokinetic model was successfully evaluated with a bootstrap analysis, Monte Carlo simulation, and an external dataset of Chinese patients (difference of 14.6% and 19.5% in measured and calculated concentrations and AUC0-24 h, respectively). Root-mean-squared-errors found in predicting the AUC0-24 h using a one- (4 h) and a two- (2 h and 7 h) limited sampling strategy were 1.60% and 0.14%, respectively. CONCLUSIONS: This developed population pharmacokinetic model can be used to calculate cycloserine concentrations and exposure in patients with multidrug-/extensively drug-resistant tuberculosis. This model was successfully validated by internal and external validation methods. This study showed that the AUC0-24 h of cycloserine can be estimated in patients with multidrug-/extensively drug-resistant tuberculosis using a 1- or 2-point limited sampling strategy in combination with the developed population pharmacokinetic model. This strategy can be used in studies to correlate drug exposure with clinical outcome. This study also showed that good target attainment rates, expressed by time above the minimal inhibitory concentration, were obtained for cycloserine with a minimal inhibitory concentration of 5 and 10 mg/L, but low rates with a minimal inhibitory concentration of 20 and 32.5 mg/L.

Physiologically Based Pharmacokinetic Modelling to Identify Pharmacokinetic Parameters Driving Drug Exposure Changes in the Elderly.

BACKGROUND: Medication use is highly prevalent with advanced age, but clinical studies are rarely conducted in the elderly, leading to limited knowledge regarding age-related pharmacokinetic changes. OBJECTIVE: The objective of this study was to investigate which pharmacokinetic parameters determine drug exposure changes in the elderly by conducting virtual clinical trials for ten drugs (midazolam, metoprolol, lisinopril, amlodipine, rivaroxaban, repaglinide, atorvastatin, rosuvastatin, clarithromycin and rifampicin) using our physiologically based pharmacokinetic (PBPK) framework. METHODS: PBPK models for all ten drugs were developed in young adults (20-50 years) following the best practice approach, before predicting pharmacokinetics in the elderly (≥ 65 years) without any modification of drug parameters. A descriptive relationship between age and each investigated pharmacokinetic parameter (peak concentration [Cmax], time to Cmax [tmax], area under the curve [AUC], clearance, volume of distribution, elimination-half-life) was derived using the final PBPK models, and verified with independent clinically observed data from 52 drugs. RESULTS: The age-related changes in drug exposure were successfully simulated for all ten drugs. Pharmacokinetic parameters were predicted within 1.25-fold (70%), 1.5-fold (86%) and 2-fold (100%) of clinical data. AUC increased progressively by 0.9% per year throughout adulthood from the age of 20 years, which was explained by decreased clearance, while Cmax, tmax and volume of distribution were not affected by human aging. Additional clinical data of 52 drugs were contained within the estimated variability of the established age-dependent correlations for each pharmacokinetic parameter. CONCLUSION: The progressive decrease in hepatic and renal blood flow, as well as glomerular filtration, rate led to a reduced clearance driving exposure changes in the healthy elderly, independent of the drug.

Effects of a rifampicin pre-treatment on linezolid pharmacokinetics.

Linezolid is an oxazolidinone antibiotic that effectively treats methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). Since rifampicin induces other antibiotic effects, it is combined with linezolid in therapeutic regimes. However, linezolid blood concentrations are reduced by this combination, which increases the risk of the emergence of antibiotic-resistant bacteria. We herein demonstrated that the combination of linezolid with rifampicin inhibited its absorption and promoted its elimination, but not through microsomal enzymes. Our results indicate that the combination of linezolid with rifampicin reduces linezolid blood concentrations via metabolic enzymes.

Individualised dosing algorithm and personalised treatment of high-dose rifampicin for tuberculosis.

AIMS: To propose new exposure targets for Bayesian dose optimisation suited for high-dose rifampicin and to apply them using measured plasma concentrations coupled with a Bayesian forecasting algorithm allowing predictions of future doses, considering rifampicin's auto-induction, saturable pharmacokinetics and high interoccasion variability. METHODS: Rifampicin exposure targets for Bayesian dose optimisation were defined based on literature data on safety and anti-mycobacterial activity in relation to rifampicin's pharmacokinetics i.e. highest plasma concentration up to 24 hours and area under the plasma concentration-time curve up to 24 hours (AUC0-24h ). Targets were suggested with and without considering minimum inhibitory concentration (MIC) information. Individual optimal doses were predicted for patients treated with rifampicin (10 mg/kg) using the targets with Bayesian forecasting together with sparse measurements of rifampicin plasma concentrations and baseline rifampicin MIC. RESULTS: The suggested exposure target for Bayesian dose optimisation was a steady state AUC0-24h of 181-214 h × mg/L. The observed MICs ranged from 0.016-0.125 mg/L (mode: 0.064 mg/L). The predicted optimal dose in patients using the suggested target ranged from 1200-3000 mg (20-50 mg/kg) with a mode of 1800 mg (30 mg/kg, n = 24). The predicted optimal doses when taking MIC into account were highly dependent on the known technical variability of measured individual MIC and the dose was substantially lower compared to when using the AUC0-24h -only target. CONCLUSIONS: A new up-to-date exposure target for Bayesian dose optimisation suited for high-dose rifampicin was derived. Using measured plasma concentrations coupled with Bayesian forecasting allowed prediction of the future dose whilst accounting for the auto-induction, saturable pharmacokinetics and high between-occasion variability of rifampicin.

Solidified SNEDDS for the oral delivery of rifampicin: Evaluation, proof of concept, in vivo kinetics, and in silico GastroPlusTM simulation.

The present investigation was performed to develop a rifampicin (RIF)-loaded solidified self-nanoemulsifying drug delivery system (SNEDDS) (solidified RIF-OF1) for in vitro and in vivo evaluations. Optimized formulations were tested for their powder flow characteristics, loading efficiency, and in vitro dissolution (at pH-1.2, 6.8 and 7.4). Compatibility studies were also performed. The formulations were also tested for hemocompatibility, intestinal permeation, histopathological effects, and in vivo pharmacokinetics. Additionally, an in silico simulation study using GastroPlus was performed. At different varied pH values, we observed immediate release (T85% within 15 min) based on the dissolution profile. This could be due to labrasol-assisted RIF solubilization. In vitro hemolysis study of the reconstituted RIF-OF1 revealed normal architecture of erythrocytes compared to the positive control (lysed and fragmented). Through in vivo permeation and biopsy studies, a rationale for facilitated intestinal permeation of RIF with components deemed physiological safe (normal anatomy of mucosal membrane evidenced from biopsy study) could be established. The in vitro-in vivo correlation (IVIVC) plus module of GastroPlusTM simulation showed a good IVIVC between in vitro release and in vivo absorption with a predicted systemic absorption of ∼96.5%. Solidified SNEDDS showed improved pharmacokinetic profiles compared to RIF suspension. Solid RIF-SNEDDS was demonstrated to be a suitable carrier for enhanced intestinal permeation and oral bioavailability. Hence, it may serve as a suitable alternative to conventional delivery systems for tuberculosis treatment.

Clinical Pharmacokinetics and Pharmacodynamics of Rifampicin in Human Tuberculosis.

The introduction of rifampicin (rifampin) into tuberculosis (TB) treatment five decades ago was critical for shortening the treatment duration for patients with pulmonary TB to 6 months when combined with pyrazinamide in the first 2 months. Resistance or hypersensitivity to rifampicin effectively condemns a patient to prolonged, less effective, more toxic, and expensive regimens. Because of cost and fears of toxicity, rifampicin was introduced at an oral daily dose of 600 mg (8-12 mg/kg body weight). At this dose, clinical trials in 1970s found cure rates of ≥ 95% and relapse rates of < 5%. However, recent papers report lower cure rates that might be the consequence of increased emergence of resistance. Several lines of evidence suggest that higher rifampicin doses, if tolerated and safe, could shorten treatment duration even further. We conducted a narrative review of rifampicin pharmacokinetics and pharmacodynamics in adults across a range of doses and highlight variables that influence its pharmacokinetics/pharmacodynamics. Rifampicin exposure has considerable inter- and intra-individual variability that could be reduced by administration during fasting. Several factors including malnutrition, HIV infection, diabetes mellitus, dose size, pharmacogenetic polymorphisms, hepatic cirrhosis, and substandard medicinal products alter rifampicin exposure and/or efficacy. Renal impairment has no influence on rifampicin pharmacokinetics when dosed at 600 mg. Rifampicin maximum (peak) concentration (Cmax) > 8.2 µg/mL is an independent predictor of sterilizing activity and therapeutic drug monitoring at 2, 4, and 6 h post-dose may aid in optimizing dosing to achieve the recommended rifampicin concentration of ≥ 8 µg/mL. A higher rifampicin Cmax is required for severe forms TB such as TB meningitis, with Cmax ≥ 22 µg/mL and area under the concentration-time curve (AUC) from time zero to 6 h (AUC6) ≥ 70 µg·h/mL associated with reduced mortality. More studies are needed to confirm whether doses achieving exposures higher than the current standard dosage could translate into faster sputum conversion, higher cure rates, lower relapse rates, and less mortality. It is encouraging that daily rifampicin doses up to 35 mg/kg were found to be safe and well-tolerated over a period of 12 weeks. High-dose rifampicin should thus be considered in future studies when constructing potentially shorter regimens. The studies should be adequately powered to determine treatment outcomes and should include surrogate markers of efficacy such as Cmax/MIC (minimum inhibitory concentration) and AUC/MIC.

Steady-state population pharmacokinetics of terizidone and its metabolite cycloserine in patients with drug-resistant tuberculosis.

AIMS: Despite terizidone being part of the second-line recommended drugs for treatment of drug-resistant tuberculosis (DR-TB), information on its pharmacokinetics is scarce. The aim of this study was to describe the steady-state population pharmacokinetics (PPK) of terizidone and its primary metabolite cycloserine in patients with DR-TB and determine the effect of patient characteristics. METHODS: This clinical study involved 39 adult DR-TB patients admitted to Brewelskloof Hospital in Cape Town, South Africa for intensive treatment phase. Blood samples were collected at predose and 0.5, 1, 2, 3, 3.5, 4, 8, 16 and 24 hours after drug administration. The estimation of PPK parameters was performed using nonlinear mixed-effects modelling software Monolix 2018R1. Free-fat mass was used to perform allometric scaling on disposition parameters. RESULTS: A 1-compartment model best described the pharmacokinetics of terizidone and cycloserine. A modified transit compartment model described the absorption of terizidone. The parameters of terizidone model were mean transit time (1.7 h), absorption rate constant (2.97 h-1 ), apparent volume of distribution (Vp/F: 13.4 L) and apparent total clearance (0.51 L h-1 ). In the joint model, apparent fraction of terizidone converted to cycloserine was 0.29 while apparent clearance of terizidone via other routes and apparent cycloserine clearance was 0.1 L h-1 and 2.94 L h-1 , respectively. Serum albumin had significant effect on Vp/F. CONCLUSIONS: The developed PPK model described well the concentration-time profile for terizidone and cycloserine in DR-TB patients. High albumin concentration was associated with low Vp/F.

Pharmacokinetics of dolutegravir 100 mg once daily with rifampicin.

BACKGROUND: Tuberculosis (TB) causes 25% of all deaths among individuals infected with human immunodeficiency virus (HIV). Rifampicin (RIF) is a potent inducer of drug metabolizing enzymes and drug transporters, and co-administration with dolutegravir (DTG) reduces DTG exposure; this can be overcome by doubling the DTG dose to 50 mg twice daily. This study investigated the effect of RIF on DTG exposure when dosed at 100 mg once daily, which could provide an easier option than 50 mg twice daily. METHODS: An open label, pharmacokinetic (PK) study was undertaken. Healthy HIV-negative subjects received DTG 50 mg for 7 days (PK1), DTG 100 mg for 7 days (PK2), RIF for 14 days, DTG 50 mg + RIF for 7 days (PK3) and DTG 100 mg + RIF for 7 days (PK4). Steady-state full DTG PK profiles were evaluated. RESULTS: DTG geometric mean ratios (GMRs) of PK3/PK1 of maximum concentration (Cmax), area under curve (AUC24h) and 24-h post-dose concentration (C24h) were 0.65 [90% confidence interval (CI) 0.55-0.75], 0.44 (90% CI 0.37-0.52) and 0.15 (0.13-90% CI 0.17), respectively. GMRs of PK4/PK1 Cmax, AUC24h and C24h were 1.09 (90% CI 0.97-1.21), 0.74 (90% CI 0.64-0.86) and 0.24 (90% CI 0.20-0.28), respectively. Median C24h of DTG 50 mg + RIF and DTG 100 mg + RIF were 251 (range 129-706) ng/mL and 140 (range 73-426) ng/mL, respectively. CONCLUSION: Although there were substantial reductions in DTG C24h when co-administered with RIF, concentrations of both DTG 50 mg and 100 mg once daily with RIF were still above the protein-binding-adjusted IC90 (drug concentration required to inhibit 90% of in-vitro viral replication) of 64 ng/mL. Further studies in HIV-TB co-infected individuals are warranted to confirm these results.