PMID- 16038474
OWN - NLM
STAT- MEDLINE
DCOM- 20050916
LR  - 20220317
IS  - 1359-6535 (Print)
IS  - 1359-6535 (Linking)
VI  - 10
IP  - 4
DP  - 2005
TI  - Are adverse events of nevirapine and efavirenz related to plasma concentrations?
PG  - 489-98
AB  - OBJECTIVE: The relationships between adverse events (AEs) and plasma 
      concentrations of nevirapine (NVP) and efavirenz (EFV) were investigated as part 
      of the large, international, randomized 2NN study. METHODS: Treatment-naive, 
      HIV-1-infected patients received NVP (once or twice daily), EFV or their 
      combination, each in combination with lamivudine and stavudine. Blood samples 
      were collected on day 3 and weeks 1, 2, 4, 24 and 48. Concentrations of NVP and 
      EFV were quantitatively assessed by a validated HPLC assay. Individual Bayesian 
      estimates of the area under the plasma concentration-time curve over 24 h 
      (AUC24h), and minimum and maximum plasma concentrations (Cmin and Cmax) as 
      measures for drug exposure of NVP and EFV, were generated using a previously 
      developed population pharmacokinetic model. Pharmacokinetic parameters were 
      compared for patients with and without central nervous system (CNS) and 
      psychiatric AEs, hepatic events, liver enzyme elevations (LEEs) and rash. 
      Furthermore, it was investigated whether a clear cut-off for a pharmacokinetic 
      parameter could be identified above which the incidence of AEs was clearly 
      increased. AEs were also related to demographic parameters and baseline 
      characteristics. RESULTS: In total, from 1077 patients, NVP (3024 samples) and 
      EFV (1694 samples) plasma concentrations and AE data (825 observations) were 
      available. For all patients Cmin, Cmax and AUC24h were determined. When corrected 
      for known covariates of gender, CD4 cell count at baseline, region, hepatitis 
      coinfection and possible interactions between these factors, no significant 
      associations between AEs and any tested exposure parameter of NVP was observed. 
      Also, no target Cmin value, above which patients were at increased risk for AEs, 
      could be established. On the other hand, geographical region, hepatitis 
      coinfection, CD4 cell count and gender were found to be significantly related 
      with the incidence of CNS and psychiatric AEs, hepatic events, LEEs and rash 
      during the treatment with NVP. The occurrence of elevated liver enzymes during 
      the first 6 weeks in the EFV-containing arm was significantly (P = 0.036) 
      correlated to the exposure of EFV (Cmin). Only hepatitis coinfection impacted on 
      LEEs during the first 6 weeks of treatment. With an EFV Cmin above 2.18 mg/l 
      during the induction phase, patients were 4.4 (range 1.3-15.5) times more at risk 
      for elevated liver enzymes. No other correlations between AEs and EFV 
      pharmacokinetics or patient characteristics could be identified. CONCLUSIONS: 
      Pharmacokinetic parameters of NVP did not have a relationship to AEs in the 2NN 
      trial when corrected for known covariates. The value of periodical drug 
      monitoring of NVP as a way to prevent toxicity is therefore limited. Treating 
      physicians should instead focus on factors that are more predictive of AEs 
      (gender, CD4 count and hepatitis coinfection). High EFV Cmin levels resulted in 
      elevated liver enzyme values during the first 6 weeks of treatment. Regular 
      measurement of EFV levels and liver enzymes at the start of therapy may therefore 
      be advised.
FAU - Kappelhoff, Bregt S
AU  - Kappelhoff BS
AD  - Department of Pharmacy et Pharmacology, Slotervaart Hospital, Amsterdam, The 
      Netherlands. apbkp@slz.nl
FAU - van Leth, Frank
AU  - van Leth F
FAU - Robinson, Patrick A
AU  - Robinson PA
FAU - MacGregor, Thomas R
AU  - MacGregor TR
FAU - Baraldi, Ezio
AU  - Baraldi E
FAU - Montella, Francesco
AU  - Montella F
FAU - Uip, David E
AU  - Uip DE
FAU - Thompson, Melanie A
AU  - Thompson MA
FAU - Russell, Darren B
AU  - Russell DB
FAU - Lange, Joep M A
AU  - Lange JM
FAU - Beijnen, Jos H
AU  - Beijnen JH
FAU - Huitema, Alwin D R
AU  - Huitema AD
CN  - 2NN Study Group
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Multicenter Study
PL  - England
TA  - Antivir Ther
JT  - Antiviral therapy
JID - 9815705
RN  - 0 (Alkynes)
RN  - 0 (Anti-HIV Agents)
RN  - 0 (Benzoxazines)
RN  - 0 (Cyclopropanes)
RN  - 0 (Oxazines)
RN  - 99DK7FVK1H (Nevirapine)
RN  - JE6H2O27P8 (efavirenz)
SB  - IM
MH  - Adult
MH  - Alkynes
MH  - Anti-HIV Agents/*adverse effects/blood/*pharmacokinetics
MH  - Benzoxazines
MH  - Central Nervous System Diseases/chemically induced
MH  - Chemical and Drug Induced Liver Injury
MH  - Cyclopropanes
MH  - Dose-Response Relationship, Drug
MH  - Drug Therapy, Combination
MH  - Exanthema/chemically induced
MH  - Female
MH  - HIV Infections/drug therapy
MH  - Humans
MH  - Male
MH  - Mental Disorders/chemically induced
MH  - Middle Aged
MH  - Nevirapine/*adverse effects/blood/*pharmacokinetics
MH  - Odds Ratio
MH  - Oxazines/*adverse effects/blood/*pharmacokinetics
EDAT- 2005/07/26 09:00
MHDA- 2005/09/17 09:00
CRDT- 2005/07/26 09:00
PHST- 2005/07/26 09:00 [pubmed]
PHST- 2005/09/17 09:00 [medline]
PHST- 2005/07/26 09:00 [entrez]
PST - ppublish
SO  - Antivir Ther. 2005;10(4):489-98.