PMID- 29133558
OWN - NLM
STAT- In-Data-Review
LR  - 20180725
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Linking)
VI  - 62
IP  - 2
DP  - 2018 Feb
TI  - Pharmacokinetics and Drug-Drug Interactions of Lopinavir-Ritonavir Administered
      with First- and Second-Line Antituberculosis Drugs in HIV-Infected Children
      Treated for Multidrug-Resistant Tuberculosis.
LID - e00420-17 [pii]
LID - 10.1128/AAC.00420-17 [doi]
AB  - Lopinavir-ritonavir forms the backbone of current first-line antiretroviral
      regimens in young HIV-infected children. As multidrug-resistant (MDR)
      tuberculosis (TB) frequently occurs in young children in high-burden TB settings,
      it is important to identify potential interactions between MDR-TB treatment and
      lopinavir-ritonavir. We describe the pharmacokinetics of and potential drug-drug 
      interactions between lopinavir-ritonavir and drugs routinely used for MDR-TB
      treatment in HIV-infected children. A combined population pharmacokinetic model
      was developed to jointly describe the pharmacokinetics of lopinavir and ritonavir
      in 32 HIV-infected children (16 with MDR-TB receiving treatment with combinations
      of high-dose isoniazid, pyrazinamide, ethambutol, ethionamide, terizidone, a
      fluoroquinolone, and amikacin and 16 without TB) who were established on a
      lopinavir-ritonavir-containing antiretroviral regimen. One-compartment models
      with first-order absorption and elimination for both lopinavir and ritonavir were
      combined into an integrated model. The dynamic inhibitory effect of the ritonavir
      concentration on lopinavir clearance was described using a maximum inhibition
      model. Even after adjustment for the effect of body weight with allometric
      scaling, a large variability in lopinavir and ritonavir exposure, together with
      strong correlations between the pharmacokinetic parameters of lopinavir and
      ritonavir, was detected. MDR-TB treatment did not have a significant effect on
      the bioavailability, clearance, or absorption rate constants of lopinavir or
      ritonavir. Most children (81% of children with MDR-TB, 88% of controls) achieved 
      therapeutic lopinavir trough concentrations (>1 mg/liter). The coadministration
      of lopinavir-ritonavir with drugs routinely used for the treatment of MDR-TB was 
      found to have no significant effect on the key pharmacokinetic parameters of
      lopinavir or ritonavir. These findings should be considered in the context of the
      large interpatient variability found in the present study and the study's modest 
      sample size.
CI  - Copyright (c) 2018 American Society for Microbiology.
FAU - van der Laan, Louvina E
AU  - van der Laan LE
AD  - Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of
      Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
      vdlaan@sun.ac.za.
FAU - Garcia-Prats, Anthony J
AU  - Garcia-Prats AJ
AD  - Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of
      Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
FAU - Schaaf, H Simon
AU  - Schaaf HS
AD  - Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of
      Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
FAU - Tikiso, Tjokosela
AU  - Tikiso T
AD  - Division of Clinical Pharmacology, Department of Medicine, University of Cape
      Town, Cape Town, South Africa.
FAU - Wiesner, Lubbe
AU  - Wiesner L
AD  - Division of Clinical Pharmacology, Department of Medicine, University of Cape
      Town, Cape Town, South Africa.
FAU - de Kock, Mine
AU  - de Kock M
AD  - Division of Clinical Pharmacology, Department of Medicine, University of Cape
      Town, Cape Town, South Africa.
FAU - Winckler, Jana
AU  - Winckler J
AD  - Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of
      Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
FAU - Norman, Jennifer
AU  - Norman J
AD  - Division of Clinical Pharmacology, Department of Medicine, University of Cape
      Town, Cape Town, South Africa.
FAU - McIlleron, Helen
AU  - McIlleron H
AD  - Division of Clinical Pharmacology, Department of Medicine, University of Cape
      Town, Cape Town, South Africa.
FAU - Denti, Paolo
AU  - Denti P
AD  - Division of Clinical Pharmacology, Department of Medicine, University of Cape
      Town, Cape Town, South Africa.
FAU - Hesseling, Anneke C
AU  - Hesseling AC
AD  - Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of
      Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
LA  - eng
GR  - U01 AI068632/AI/NIAID NIH HHS/United States
GR  - UM1 AI068632/AI/NIAID NIH HHS/United States
GR  - UM1 AI068634/AI/NIAID NIH HHS/United States
GR  - UM1 AI106701/AI/NIAID NIH HHS/United States
GR  - UM1 AI068636/AI/NIAID NIH HHS/United States
PT  - Journal Article
DEP - 20180125
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
PMC - PMC5786799
OTO - NOTNLM
OT  - Mycobacterium tuberculosis
OT  - antiretroviral agents
OT  - drug interactions
OT  - human immunodeficiency virus
OT  - multidrug resistance
OT  - pediatric drug therapy
OT  - pediatric infectious disease
OT  - pharmacokinetics
OT  - population pharmacokinetics
EDAT- 2017/11/15 06:00
MHDA- 2017/11/15 06:00
CRDT- 2017/11/15 06:00
PHST- 2017/02/27 00:00 [received]
PHST- 2017/10/13 00:00 [accepted]
PHST- 2017/11/15 06:00 [pubmed]
PHST- 2017/11/15 06:00 [medline]
PHST- 2017/11/15 06:00 [entrez]
AID - AAC.00420-17 [pii]
AID - 10.1128/AAC.00420-17 [doi]
PST - epublish
SO  - Antimicrob Agents Chemother. 2018 Jan 25;62(2). pii: AAC.00420-17. doi:
      10.1128/AAC.00420-17. Print 2018 Feb.