Population Pharmacokinetics and Dosing of Ethionamide in Children with Tuberculosis

ABSTRACT Ethionamide has proven efficacy against both drug-susceptible and some drug-resistant strains of Mycobacterium tuberculosis. Limited information on its pharmacokinetics in children is available, and current doses are extrapolated from weight-based adult doses. Pediatric doses based on more robust evidence are expected to improve antituberculosis treatment, especially in small children. In this analysis, ethionamide concentrations in children from 2 observational clinical studies conducted in Cape Town, South Africa, were pooled. All children received ethionamide once daily at a weight-based dose of approximately 20 mg/kg of body weight (range, 10.4 to 25.3 mg/kg) in combination with other first- or second-line antituberculosis medications and with antiretroviral therapy in cases of HIV coinfection. Pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. The MDR-PK1 study contributed data for 110 children on treatment for multidrug-resistant tuberculosis, while the DATiC study contributed data for 9 children treated for drug-susceptible tuberculosis. The median age of the children in the studies combined was 2.6 years (range, 0.23 to 15 years), and the median weight was 12.5 kg (range, 2.5 to 66 kg). A one-compartment, transit absorption model with first-order elimination best described ethionamide pharmacokinetics in children. Allometric scaling of clearance (typical value, 8.88 liters/h), the volume of distribution (typical value, 21.4 liters), and maturation of clearance and absorption improved the model fit. HIV coinfection decreased the ethionamide bioavailability by 22%, rifampin coadministration increased clearance by 16%, and ethionamide administration by use of a nasogastric tube increased the rate, but the not extent, of absorption. The developed model was used to predict pediatric doses achieving the same drug exposure achieved in 50- to 70-kg adults receiving 750-mg once-daily dosing. Based on model predictions, we recommend a weight-banded pediatric dosing scheme using scored 125-mg tablets.

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Preclinical Evaluations To Identify Optimal Linezolid Regimens for Tuberculosis Therapy

mBio ◽

10.1128/mbio.01741-15 ◽

2015 ◽

Vol 6 (6) ◽

Cited By ~ 28

Author(s):

Ashley N. Brown ◽

George L. Drusano ◽

Jonathan R. Adams ◽

Jaime L. Rodriquez ◽

Kalyani Jambunathan ◽

...

Keyword(s):

Antibacterial Activity ◽

Resistant Mutant ◽

Multidrug Resistant ◽

Pharmacokinetic Parameters ◽

Optimal Dosage ◽

Dependent Manner ◽

Once Daily ◽

Content Type ◽

Toxicity Relationship

ABSTRACT Linezolid is an oxazolidinone with potent activity against Mycobacterium tuberculosis. Linezolid toxicity in patients correlates with the dose and duration of therapy. These toxicities are attributable to the inhibition of mitochondrial protein synthesis. Clinically relevant linezolid regimens were simulated in the in vitro hollow-fiber infection model (HFIM) system to identify the linezolid therapies that minimize toxicity, maximize antibacterial activity, and prevent drug resistance. Linezolid inhibited mitochondrial proteins in an exposure-dependent manner, with toxicity being driven by trough concentrations. Once-daily linezolid killed M. tuberculosis in an exposure-dependent manner. Further, 300 mg linezolid given every 12 hours generated more bacterial kill but more toxicity than 600 mg linezolid given once daily. None of the regimens prevented linezolid resistance. These findings show that with linezolid monotherapy, a clear tradeoff exists between antibacterial activity and toxicity. By identifying the pharmacokinetic parameters linked with toxicity and antibacterial activity, these data can provide guidance for clinical trials evaluating linezolid in multidrug antituberculosis regimens. IMPORTANCE The emergence and spread of multidrug-resistant M. tuberculosis are a major threat to global public health. Linezolid is an oxazolidinone that is licensed for human use and has demonstrated potent activity against multidrug-resistant M. tuberculosis. However, long-term use of linezolid has shown to be toxic in patients, often resulting in thrombocytopenia. We examined therapeutic linezolid regimens in an in vitro model to characterize the exposure-toxicity relationship. The antibacterial activity against M. tuberculosis was also assessed for these regimens, including the amplification or suppression of resistant mutant subpopulations by the chosen regimen. Higher exposures of linezolid resulted in greater antibacterial activity, but with more toxicity and, for some regimens, increased resistant mutant subpopulation amplification, illustrating the trade-off between activity and toxicity. These findings can provide valuable insight for designing optimal dosage regimens for linezolid that are part of the long combination courses used to treat multidrug-resistant M. tuberculosis.

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Pharmacokinetics of 2,000 Milligram Ertapenem in Tuberculosis Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02250-17 ◽

2018 ◽

Vol 62 (5) ◽

Cited By ~ 3

Author(s):

M. A. Zuur ◽

S. Ghimire ◽

M. S. Bolhuis ◽

A. M. A. Wessels ◽

R. van Altena ◽

...

Keyword(s):

Central Compartment ◽

Multidrug Resistant ◽

Volume Of Distribution ◽

Interindividual Variation ◽

Infection Model ◽

Time Curve ◽

Once Daily ◽

Content Type ◽

Drug Concentrations ◽

Liquid Chromatography Tandem Mass

ABSTRACT Ertapenem is a carbapenem antibiotic with activity against Mycobacterium tuberculosis . Dose simulations in a hollow-fiber infection model showed that 2,000 mg once daily is an appropriate dose to be tested in clinical studies. Before using this dose in a phase II study, the aim of this prospective pharmacokinetic study was to confirm the pharmacokinetics of 2,000 mg once daily in tuberculosis (TB) patients. Twelve TB patients received a single intravenous dose of 2,000 mg ertapenem as a 30-min infusion. Blood samples were collected at 0, 0.5, 1, 2, 3, 4, 8, 12, and 24 h postadministration. Drug concentrations were measured using a validated liquid chromatography-tandem mass spectrometry assay. A large interindividual variation in the pharmacokinetics of ertapenem was observed. The median (interquartile range) area under the plasma concentration-time curve to infinity (AUC 0–∞ ) was 2,032 (1,751 to 2,346) mg · h/liter, the intercompartmental clearance (CL 12 ) was 1.941 (0.979 to 2.817) liters/h, and the volume of distribution in the central compartment ( V 1 ) was 1.514 (1.064 to 2.210) liters. A more than dose-proportional increase in AUC was observed compared to results reported for 1,000 mg ertapenem in multidrug-resistant TB patients. Based on a MIC of 1.0 mg/liter, 11 out of 12 patients would have reached the target value of unbound drug exceeding the MIC over 40% of the time ( f 40% T >MIC). In conclusion, this study shows that 2,000 mg ertapenem once daily in TB patients reached the expected f 40% T >MIC for most of the patients, and exploration in a phase 2 study can be advocated.

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Population Pharmacokinetics of Bedaquiline (TMC207), a Novel Antituberculosis Drug

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01418-13 ◽

2014 ◽

Vol 58 (9) ◽

pp. 5315-5324 ◽

Cited By ~ 22

Author(s):

Sarah C. McLeay ◽

Peter Vis ◽

Rolf P. G. van Heeswijk ◽

Bruce Green

Keyword(s):

Apparent Volume ◽

Multidrug Resistant ◽

Volume Of Distribution ◽

Population Pharmacokinetic ◽

Time Data ◽

Content Type ◽

Mixed Effects Modeling ◽

Phase Ii Studies ◽

Apparent Clearance ◽

Residual Unexplained Variability

ABSTRACTBedaquiline is a novel agent for the treatment of pulmonary multidrug-resistantMycobacterium tuberculosisinfections, in combination with other agents. The objective of this study was to develop a population pharmacokinetic (PK) model for bedaquiline to describe the concentration-time data from phase I and II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant tuberculosis (TB). A total of 5,222 PK observations from 480 subjects were used in a nonlinear mixed-effects modeling approach. The PK was described with a 4-compartment disposition model with dual zero-order input (to capture dual peaks observed during absorption) and long terminal half-life (t1/2). The model included between-subject variability on apparent clearance (CL/F), apparent central volume of distribution (Vc/F), the fraction of dose via the first input, and bioavailability (F). Bedaquiline was widely distributed, with apparent volume at steady state of >10,000 liters and low clearance. The long terminalt1/2was likely due to redistribution from the tissue compartments. The final covariate model adequately described the data and had good simulation characteristics. The CL/F was found to be 52.0% higher for subjects of black race than that for subjects of other races, andVc/F was 15.7% lower for females than that for males, although their effects on bedaquiline exposure were not considered to be clinically relevant. Small differences in F and CL/F were observed between the studies. The residual unexplained variability was 20.6% and was higher (27.7%) for long-term phase II studies.

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Steady-State Plasma and Intrapulmonary Pharmacokinetics and Pharmacodynamics of Cethromycin

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.9.3508-3515.2004 ◽

2004 ◽

Vol 48 (9) ◽

pp. 3508-3515 ◽

Cited By ~ 17

Author(s):

John E. Conte ◽

Jeffrey A. Golden ◽

Juliana Kipps ◽

Elisabeth Zurlinden

Keyword(s):

Steady State ◽

Half Life ◽

Dose Group ◽

Drug Exposure ◽

Pharmacokinetic Parameters ◽

Multiple Time ◽

Respiratory Pathogens ◽

Once Daily ◽

Standard Deviations ◽

State Plasma

ABSTRACT The objective of this study was to determine the steady-state plasma and intrapulmonary pharmacokinetic parameters of orally administered cethromycin in healthy volunteers. The study design included administering 150 or 300 mg of cethromycin once daily to 25 or 35 healthy adult subjects, respectively, for a total of five doses. Standardized and timed bronchoalveolar lavage (BAL) was performed after the last dose. Blood was obtained for drug assay prior to the first and last dose, at multiple time points following the last dose, and at the time of BAL. Cethromycin was measured in plasma, BAL, and alveolar cell (AC) by using a combined high-performance liquid chromatography-mass spectrometric technique. Plasma, epithelial lining fluid (ELF), and AC pharmacokinetics were derived by noncompartmental methods. C max/90% minimum inhibitory concentration (MIC90) ratios, area under the concentration-time curve (AUC)/MIC90 ratios, intrapulmonary drug exposure ratios, and percent time above MIC90 during the dosing interval (%T > MIC90) were calculated for recently reported respiratory pathogens. The kinetics were nonlinear, i.e., not proportional to dose. In the 150-mg-dose group, the C max (mean ± standard deviations), AUC0-24, and half-life for plasma were 0.181 ± 0.084 μg/ml, 0.902 ± 0.469 μg · h/ml, and 4.85 ± 1.10 h, respectively; for ELF the values were 0.9 ± 0.2 μg/ml, 11.4 μg · h/ml, and 6.43 h, respectively; for AC the values were 12.7 ± 6.4 μg/ml, 160.8 μg · h/ml, and 10.0 h, respectively. In the 300-mg-dose group, the C max (mean ± standard deviations), AUC0-24, and half-life for plasma were 0.500 ± 0.168 μg/ml, 3.067 ± 1.205 μg · h/ml, and 4.94 ± 0.66 h, respectively; for ELF the values were 2.7 ± 2.0 μg/ml, 24.15 μg · h/ml, and 5.26 h, respectively; for AC the values were 55.4 ± 38.7 μg/ml, 636.2 μg · h/ml, and 11.6 h, respectively. We concluded that the C max/MIC90 ratios, AUC/MIC90 ratios, %T > MIC90 values, and extended plasma and intrapulmonary half-lives provide a pharmacokinetic rationale for once-daily administration and are favorable for the treatment of cethromycin-susceptible pulmonary infections.

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Urinary Concentrations of Colistimethate and Formed Colistin after Intravenous Administration in Patients with Multidrug-Resistant Gram-Negative Bacterial Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02595-16 ◽

2017 ◽

Vol 61 (8) ◽

Cited By ~ 12

Author(s):

Sonia Luque ◽

Carol Escaño ◽

Luisa Sorli ◽

Jian Li ◽

Nuria Campillo ◽

...

Keyword(s):

Urinary Excretion ◽

Intravenous Administration ◽

Bacterial Infections ◽

High Performance ◽

Multidrug Resistant ◽

Limited Information ◽

Urinary Recovery ◽

Gram Negative ◽

Content Type ◽

Colistimethate Sodium

ABSTRACT Limited information is available on the urinary excretion of colistin in infected patients. This study aimed to investigate the pharmacokinetics of colistimethate sodium (CMS) and formed colistin in urine in patients with multidrug-resistant (MDR) Gram-negative bacterial infections. A pharmacokinetic study was conducted on 12 patients diagnosed with an infection caused by an extremely drug-resistant (XDR) P. aeruginosa strain and treated with intravenous CMS. Fresh urine samples were collected at 2-h intervals, and blood samples were collected predose (C min ss) and at the end of the CMS infusion (C max ss) for measurement of concentrations of CMS and formed colistin using high-performance liquid chromatography (HPLC). CMS urinary recovery was determined as the summed amount of CMS and formed colistin recovered in urine for each 2-h interval divided by the CMS dose. There were 12 enrolled patients, 9 of whom were male (75%). Data [median (range)] were as follows: age, 65.5 (37 to 86) years; colistimethate urinary recovery 0 to 6 h, 42.6% (2.9% to 72.8%); range of concentrations of colistin in urine, <0.1 to 95.4 mg/liter; C min ss and C max ss of colistin in plasma, 0.9 (<0.2 to 1.4) and 0.9 (<0.2 to 1.4) mg/liter, respectively. In 6/12 (50%) patients, more than 40% of the CMS dose was recovered in the urine within the first 6 h after CMS administration. This study demonstrated rapid urinary excretion of CMS in patients within the first 6 h after intravenous administration. In all but one patient, the concentrations of formed colistin in urine were above the MIC for the most predominant isolate of P. aeruginosa in our hospital. Future studies are warranted for optimizing CMS dosage regimens in urinary tract infection (UTI) patients.

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JPC-2997, a New Aminomethylphenol with HighIn VitroandIn VivoAntimalarial Activities against Blood Stages of Plasmodium

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03762-14 ◽

2014 ◽

Vol 59 (1) ◽

pp. 170-177 ◽

Cited By ~ 10

Author(s):

Geoffrey W. Birrell ◽

Marina Chavchich ◽

Arba L. Ager ◽

Hong-Ming Shieh ◽

Gavin D. Heffernan ◽

...

Keyword(s):

Half Life ◽

Multidrug Resistant ◽

Volume Of Distribution ◽

Parasite Line ◽

Content Type ◽

Elimination Half Life ◽

Highly Active ◽

Elimination Half

ABSTRACT4-(tert-Butyl)-2-((tert-butylamino)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)-phenol (JPC-2997) is a new aminomethylphenol compound that is highly activein vitroagainst the chloroquine-sensitive D6, the chloroquine-resistant W2, and the multidrug-resistant TM90-C2BPlasmodium falciparumlines, with 50% inhibitory concentrations (IC50s) ranging from 7 nM to 34 nM. JPC-2997 is >2,500 times less cytotoxic (IC50s > 35 μM) to human (HepG2 and HEK293) and rodent (BHK) cell lines than the D6 parasite line. In comparison to the chemically related WR-194,965, a drug that had advanced to clinical studies, JPC-2997 was 2-fold more activein vitroagainstP. falciparumlines and 3-fold less cytotoxic. The compound possesses potentin vivosuppression activity againstPlasmodium berghei, with a 50% effective dose (ED50) of 0.5 mg/kg of body weight/day following oral dosing in the Peters 4-day test. The radical curative dose of JPC-2997 was remarkably low, at a total dose of 24 mg/kg, using the modified Thompson test. JPC-2997 was effective in curing threeAotusmonkeys infected with a chloroquine- and pyrimethamine-resistant strain ofPlasmodium vivaxat a dose of 20 mg/kg daily for 3 days. At the doses administered, JPC-2997 appeared to be well tolerated in mice and monkeys. Preliminary studies of JPC-2997 in mice show linear pharmacokinetics over the range 2.5 to 40 mg/kg, a low clearance of 0.22 liters/h/kg, a volume of distribution of 15.6 liters/kg, and an elimination half-life of 49.8 h. The highin vivopotency data and lengthy elimination half-life of JPC-2997 suggest that it is worthy of further preclinical assessment as a partner drug.

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Absence of Effect of Rufloxacin on Theophylline Pharmacokinetics in Steady State

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.9.2359 ◽

1998 ◽

Vol 42 (9) ◽

pp. 2359-2364 ◽

Cited By ~ 6

Author(s):

Martina Kinzig-Schippers ◽

Uwe Fuhr ◽

Marina Cesana ◽

Carola Müller ◽

A. Horst Staib ◽

...

Keyword(s):

Steady State ◽

Adverse Events ◽

Compartment Model ◽

Volume Of Distribution ◽

Reversed Phase ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Elimination Phase ◽

Once Daily ◽

Model Independent

ABSTRACT Several quinolone antibacterial agents are known to inhibit the metabolism of theophylline, with the potential to cause adverse events due to raised theophylline concentrations during coadministration. A randomized crossover study was therefore conducted with 12 healthy male volunteers (ages, 23 to 34 years; body weight, 64 to 101 kg) to evaluate a possible interaction between rufloxacin and theophylline. Both drugs were administered at steady state. Following the administration of an oral loading dose of 400 mg on day 1, rufloxacin was given orally at 200 mg once daily on days 2 to 7 during one period only. During both periods, 146 mg of theophylline was administered orally twice daily for 3 days (which were days 4 to 6 of the rufloxacin coadministration period) and intravenously once the next morning to test for an interaction. Theophylline and rufloxacin concentrations were measured by reversed-phase high-pressure liquid chromatography, the pharmacokinetics of theophylline at steady state following administration of the last dose were calculated by compartment-model-independent methods. To compare the treatments, analysis of variance-based point estimates and 90% confidence intervals (given in parentheses) were calculated for the mean ratios of the pharmacokinetic parameters from the test (rufloxacin coadministration) over those from the reference (theophylline without rufloxacin) period. These were as follows: maximum concentration at steady state, 1.01 (0.96 to 1.07); area under the concentration-time curve from 0 to 12 h, 0.98 (0.94 to 1.02); half-life, 0.99 (0.95 to 1.03); total clearance at steady state, 1.02 (0.99 to 1.06); and volume of distribution in the elimination phase, 1.01 (0.97 to 1.05). In conclusion, rufloxacin did not affect theophylline pharmacokinetics at steady state. Therefore, therapeutic coadministration of rufloxacin and theophylline is not expected to cause an increased incidence of theophylline-related adverse events.

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Phase I/II Trial of the Pharmacokinetics, Safety, and Antiretroviral Activity of Tenofovir Disoproxil Fumarate in Human Immunodeficiency Virus-Infected Adults

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.10.2733-2739.2001 ◽

2001 ◽

Vol 45 (10) ◽

pp. 2733-2739 ◽

Cited By ~ 235

Author(s):

Patricia Barditch-Crovo ◽

Steven G. Deeks ◽

Ann Collier ◽

Sharon Safrin ◽

Dion F. Coakley ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Drug Exposure ◽

Pharmacokinetic Parameters ◽

Drug Discontinuation ◽

Double Blind ◽

Once Daily ◽

Immunodeficiency Virus ◽

Tenofovir Df ◽

Hiv 1 ◽

Dose Proportional

ABSTRACT Tenofovir DF is an antiviral nucleotide with activity against human immunodeficiency virus type 1 (HIV-1). The pharmacokinetics, safety, and activity of oral tenofovir DF in HIV-1-infected adults were evaluated in a randomized, double-blind, placebo-controlled, escalating-dose study of four doses (75, 150, 300, and 600 mg given once daily). Subjects received a single dose of tenofovir DF or a placebo, followed by a 7-day washout period. Thereafter, subjects received their assigned study drug once daily for 28 days. Pharmacokinetic parameters were dose proportional and demonstrated no change with repeated dosing. Reductions in plasma HIV-1 RNA were dose related at tenofovir DF doses of 75 to 300 mg, but there was no increase in virus suppression between the 300- and 600-mg dose cohorts, despite dose-proportional increases in drug exposure. Grade III or IV adverse events were limited to laboratory abnormalities, including elevated creatine phosphokinase and liver function tests, which resolved with or without drug discontinuation and without sequelae. No patients developed detectable sequence changes in the reverse transcriptase gene.

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Pharmacokinetics and Tolerability of Daptomycin at Doses up to 12 Milligrams per Kilogram of Body Weight Once Daily in Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00247-06 ◽

2006 ◽

Vol 50 (10) ◽

pp. 3245-3249 ◽

Cited By ~ 228

Author(s):

Mark Benvenuto ◽

David P. Benziger ◽

Sara Yankelev ◽

Gloria Vigliani

Keyword(s):

Body Weight ◽

Healthy Volunteers ◽

Bloodstream Infections ◽

Volume Of Distribution ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Once Daily ◽

Complicated Skin ◽

Multiple Dose Pharmacokinetics ◽

Dose Proportional

ABSTRACT Daptomycin, a novel lipopeptide, is bactericidal against a broad range of gram-positive strains, including methicillin- (MRSA) and vancomycin-resistant Staphylococcus aureus. Daptomycin is approved at 4 mg/kg of body weight given intravenously once daily for the treatment of complicated skin and skin structure infections and at 6 mg/kg for the treatment of S. aureus bloodstream infections (bacteremia), including right-sided endocarditis caused by methicillin-susceptible S. aureus and MRSA. The present study was designed to evaluate the multiple-dose pharmacokinetics and safety of daptomycin at doses of 6 to 12 mg/kg in healthy volunteers. Three cohorts of 12 subjects each were given daptomycin (10 mg/kg) or placebo once daily for 14 days, daptomycin (12 mg/kg) or placebo once daily for 14 days, or daptomycin (6 or 8 mg/kg) once daily for 4 days. Daptomycin produced dose-proportional increases in the area under the plasma concentration-time curve and in trough daptomycin levels and nearly dose-proportional increases in peak daptomycin concentrations. Other pharmacokinetic parameters measured on day 1 and at steady state were independent of the dose, including the half-life (approximately 8 h), weight-normalized plasma clearance (9 to 10 ml/h/kg), and volume of distribution (approximately 100 ml/kg). Plasma protein binding was 90% to 93% and was independent of the daptomycin concentration. Daptomycin did not produce electrocardiographic abnormalities or electrophysiological evidence of muscle or nerve toxicity. Daptomycin was well tolerated in subjects dosed with up to 12 mg/kg intravenously for 14 days. Doses of daptomycin higher than 6 mg/kg once daily may be considered in further studies to evaluate the safety and efficacy of daptomycin in difficult-to-treat infections.

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Impact of Lopinavir-Ritonavir or Nevirapine on Bedaquiline Exposures and Potential Implications for Patients with Tuberculosis-HIV Coinfection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03246-14 ◽

2014 ◽

Vol 58 (11) ◽

pp. 6406-6412 ◽

Cited By ~ 37

Author(s):

Elin M. Svensson ◽

Kelly E. Dooley ◽

Mats O. Karlsson

Keyword(s):

Safety Concern ◽

Plasma Concentrations ◽

Multidrug Resistant ◽

Antiretroviral Drugs ◽

Relative Standard Error ◽

Concomitant Treatment ◽

Mixed Effects Modeling ◽

Hiv Coinfection ◽

Relative Standard ◽

Mdr Tb

ABSTRACTConcomitant treatment of tuberculosis (TB) and HIV is recommended and improves outcomes. Bedaquiline is a novel drug for the treatment of multidrug-resistant (MDR) TB; combined use with antiretroviral drugs, nevirapine, or ritonavir-boosted lopinavir (LPV/r) is anticipated, but no clinical data from coinfected patients are available. Plasma concentrations of bedaquiline and its M2 metabolite after single doses were obtained from interaction studies with nevirapine or LPV/r in healthy volunteers. The antiretrovirals' effects on bedaquiline and M2 pharmacokinetics were assessed by nonlinear mixed-effects modeling. Potential dose adjustments were evaluated with simulations. No significant effects of nevirapine on bedaquiline pharmacokinetics were identified. LPV/r decreased bedaquiline and M2 clearances to 35% (relative standard error [RSE], 9.2%) and 58% (RSE, 8.4%), respectively, of those without comedication. As almost 3-fold (bedaquiline) and 2-fold (M2) increases in exposures during chronic treatment with LPV/r are expected, dose adjustments are suggested for evaluation. Efficacious, safe bedaquiline dosing for MDR-TB patients receiving antiretrovirals is important. Modeling results suggest that bedaquiline can be coadministered with nevirapine without dose adjustments. The predicted elevation of bedaquiline and M2 levels during LPV/r coadministration may be a safety concern, and careful monitoring is recommended. Further data are being collected in coinfected patients to determine whether dose adjustments are needed. (These studies have been registered at ClinicalTrials.gov under registration numbers NCT00828529 [study C110] and NCT00910806 [study C117].)

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