2. Academic Validation
  3. Population Pharmacokinetics of Cycloserine and Pharmacokinetic/Pharmacodynamic Target Attainment in Multidrug-Resistant Tuberculosis Patients Dosed with Terizidone

Population Pharmacokinetics of Cycloserine and Pharmacokinetic/Pharmacodynamic Target Attainment in Multidrug-Resistant Tuberculosis Patients Dosed with Terizidone

  • Antimicrob Agents Chemother. 2020 Oct 20;64(11):e01381-20. doi: 10.1128/AAC.01381-20.
Maxwell T Chirehwa 1,  Richard Court 1,  Mariana de Kock 2,  Lubbe Wiesner 1,  Nihal de Vries 3,  Joseph Harding 4,  Tawanda Gumbo 5,  Gary Maartens 1 6,  Rob Warren 2,  Paolo Denti 1,  Helen McIlleron 7 6
Affiliations

Affiliations

  • 1 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
  • 2 NRF-DSI Centre of Excellence in Biomedical Tuberculosis Research, SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa.
  • 3 Brooklyn Chest Hospital, Cape Town, South Africa.
  • 4 DP Marais Hospital, Cape Town, South Africa.
  • 5 Praedicare, Dallas, Texas, USA.
  • 6 Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
  • 7 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa [email protected].
PMID: 32816738 DOI: 10.1128/AAC.01381-20
Abstract

Cycloserine is a WHO group B drug for the treatment of multidrug-resistant tuberculosis (TB). Pharmacokinetic/pharmacodynamic data for cycloserine when dosed as terizidone are sparse. The aim of this analysis was to describe the population pharmacokinetics of cycloserine when administered as terizidone and predict the doses of terizidone attaining cycloserine exposures associated with efficacy. The plasma cycloserine level was measured 2 to 6 weeks after treatment initiation in patients hospitalized for second-line tuberculosis treatment. The pretreatment MICs of cycloserine were determined for the clinical isolates. We enrolled 132 participants with rifampicin-resistant TB; 79 were HIV positive. The median pretreatment MIC was 16 mg/liter. A one-compartment disposition model with two clearance pathways, nonrenal (0.35 liters/h) and renal (0.43 liters/h), described cycloserine pharmacokinetics well. Nonrenal clearance and the volume of distribution were allometrically scaled using fat-free mass. Smoking increased nonrenal clearance by 41%. Simulations showed that with daily doses of terizidone (750 mg and 1,000 mg for patients weighing ≤45 kg and >45 kg, respectively), the probability of maintaining the plasma cycloserine concentration above the MIC for more than 30% of the dosing interval (30% T>MIC) (which is associated with a 1.0-log10-CFU/ml kill in vitro) exceeded 90% at MIC values of ≤16 mg/liter, but the proportion of patients achieving 100% T>MIC (which is associated with the prevention of resistance) was more than 90% only at MICs of ≤8 mg/liter. Based on a target derived in vitro, the WHO-recommended doses of terizidone are effective for cycloserine MICs of ≤8 mg/liter, and higher doses are required to prevent the development of resistance.

Keywords

MIC; cycloserine; pharmacodynamics; population pharmacokinetics; probability of target attainment; terizidone.

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