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Relationship between Plasma and Intracellular Concentrations of Bedaquiline and Its M2 Metabolite in South African Patients with Rifampin-Resistant Tuberculosis
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- Ngwalero, Precious (författare)
- Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.
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- Brust, James C. M. (författare)
- Albert Einstein Coll Med, Bronx, NY 10467 USA.;Montefiore Med Ctr, 111 E 210th St, Bronx, NY 10467 USA.
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- van Beek, Stijn W. (författare)
- Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.
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- Wasserman, Sean (författare)
- Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa.;Univ Cape Town, Dept Med, Cape Town, South Africa.
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- Maartens, Gary (författare)
- Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.;Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa.;Univ Cape Town, Dept Med, Cape Town, South Africa.
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- Meintjes, Graeme (författare)
- Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa.;Univ Cape Town, Dept Med, Cape Town, South Africa.
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- Joubert, Anton (författare)
- Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.
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- Norman, Jennifer (författare)
- Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.
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- Castel, Sandra (författare)
- Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.
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- Gandhi, Neel R. (författare)
- Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA.;Emory Univ, Emory Sch Med, Atlanta, GA 30322 USA.
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- Denti, Paolo (författare)
- Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.
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- McIlleron, Helen (författare)
- Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.;Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa.;Univ Cape Town, Dept Med, Cape Town, South Africa.
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- Svensson, Elin, 1985- (författare)
- Uppsala universitet,Institutionen för farmaci,Institutionen för farmaceutisk biovetenskap,Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.
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- Wiesner, Lubbe (författare)
- Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.
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Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa Albert Einstein Coll Med, Bronx, NY 10467 USA.;Montefiore Med Ctr, 111 E 210th St, Bronx, NY 10467 USA. (creator_code:org_t)
- American Society for Microbiology, 2021
- 2021
- Engelska.
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Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 65:11
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Bedaquiline is recommended for the treatment of all patients with rifampin-resistant tuberculosis (RR-TB). Bedaquiline accumulates within cells, but its intracellular pharmacokinetics have not been characterized, which may have implications for dose optimization. We developed a novel assay using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the intracellular concentrations of bedaquiline and its primary metabolite M2 in patients with RR-TB in South Africa. Twenty-one participants were enrolled and underwent sparse sampling of plasma and peripheral blood mononuclear cells (PBMCs) at months 1, 2, and 6 of treatment and at 3 and 6 months after bedaquiline treatment completion. Intensive sampling was performed at month 2. We used noncompartmental analysis to describe plasma and intracellular exposures and a population pharmacokinetic model to explore the relationship between plasma and intracellular pharmacokinetics and the effects of key covariates. Bedaquiline concentrations from month 1 to month 6 of treatment ranged from 94.7 to 2,540 ng/ml in plasma and 16.2 to 5,478 ng/ml in PBMCs, and concentrations of M2 over the 6-month treatment period ranged from 34.3 to 496 ng/ml in plasma and 109.2 to 16,764 ng/ml in PBMCs. Plasma concentrations of bedaquiline were higher than those of M2, but intracellular concentrations of M2 were considerably higher than those of bedaquiline. In the pharmacokinetic modeling, we estimated a linear increase in the intracellular-plasma accumulation ratio for bedaquiline and M2, reaching maximum effect after 2 months of treatment. The typical intracellular-plasma ratios 1 and 2 months after start of treatment were 0.61 (95% confidence interval [CI]: 0.42 to 0.92) and 1.10 (95% CI: 0.74 to 1.63) for bedaquiline and 12.4 (95% CI: 8.8 to 17.8) and 22.2 (95% CI: 15.6 to 32.3) for M2. The intracellular-plasma ratios for both bedaquiline and M2 were decreased by 54% (95% CI: 24 to 72%) in HIV-positive patients compared to HIV-negative patients. Bedaquiline and M2 were detectable in PBMCs 6 months after treatment discontinuation. M2 accumulated at higher concentrations intracellularly than bedaquiline, supporting in vitro evidence that M2 is the main inducer of phospholipidosis.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Mikrobiologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Microbiology in the medical area (hsv//eng)
Nyckelord
- drug-resistant tuberculosis
- bedaquiline
- metabolite
- intracellular
- pharmacokinetics
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Till lärosätets databas
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Ngwalero, Precio ...
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Brust, James C. ...
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van Beek, Stijn ...
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Wasserman, Sean
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Maartens, Gary
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Meintjes, Graeme
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visa fler...
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Joubert, Anton
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Norman, Jennifer
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Castel, Sandra
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Gandhi, Neel R.
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Denti, Paolo
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McIlleron, Helen
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Svensson, Elin, ...
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Wiesner, Lubbe
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