Effect of food on the steady-state pharmacokinetics of delavirdine in patients with HIV infection

Gene D. Morse, Margaret A Fischl, Mark J. Shelton, Steve R. Cox, Leslie Thompson, Andrew A. Della-Coletta, William W. Freimuth

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Abstract

Objective: In a prior single-dose study that examined the effect of food on delavirdine pharmacokinetics in healthy volunteers, the absorption of delavirdine mesylate was delayed and the area under the curve was reduced by 26% in the presence of food. Since the complex, nonlinear pharmacokinetics of delavirdine do not permit a simple extrapolation of the results of a single-dose study to steady state, the present multiple-dose study was performed. Patients and study design: Thirteen stable patients with HIV-1 infection (two females, 11 males; CD4 count range 124-588 cells/mm3) completed a randomised, crossover study in which subjects received two 14-day treatments with delavirdine mesylate 400mg every 8 hours. In treatment A, all delavirdine doses were administered on an empty stomach and in treatment B were taken with food. A pharmacokinetic evaluation was performed on day 14 of each treatment period. Setting: An ambulatory AIDS research centre in an academic medical centre. Interventions: Administration of delavirdine with and without food. Main outcome measures: Pharmacokinetic parameters for delavirdine. Results: The maximum concentration (Cmax) [± standard deviation] in treatment A was 29.6 ± 13.6μM and in treatment B it was 23.0 ± 8.61μM (p = 0.037). The minimum concentrations (Cmin) were 9.45 ± 6.7μM and 11.2 ± 9.2μM, respectively (p > 0.05). The oral clearances (CLoral) were 17.8 ± 41.6 L/h (treatment A) and 18.5 ± 39.0 L/h (treatment B) [p > 0.05]. Similar patterns were observed for N-dealkylated delavirdine with a significant difference only in Cmax (4.13 vs 3.47μM [p = 0.022], treatment A vs B). Conclusions: These findings indicated that, in contrast to the increased CLoral noted in a prior single-dose study, food did not have a significant effect at steady state on the area under the plasma concentration-time curve or Cmin. Although Cmax was significantly lower when the drug was taken taken with food, the clinical relevance of this parameter as compared with the trough concentration is unclear since the current focus for antiretrovirals is on maintaining trough concentrations in excess of in vitro inhibitory concentrations.

Original languageEnglish
Pages (from-to)255-261
Number of pages7
JournalClinical Drug Investigation
Volume23
Issue number4
DOIs
StatePublished - May 1 2003

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Delavirdine
HIV Infections
Pharmacokinetics
Food
Therapeutics
CD4 Lymphocyte Count
Cross-Over Studies
Area Under Curve
HIV-1
Stomach
Healthy Volunteers
Acquired Immunodeficiency Syndrome

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

Effect of food on the steady-state pharmacokinetics of delavirdine in patients with HIV infection. / Morse, Gene D.; Fischl, Margaret A; Shelton, Mark J.; Cox, Steve R.; Thompson, Leslie; Della-Coletta, Andrew A.; Freimuth, William W.

In: Clinical Drug Investigation, Vol. 23, No. 4, 01.05.2003, p. 255-261.

Research output: Contribution to journalArticle

Morse, Gene D. ; Fischl, Margaret A ; Shelton, Mark J. ; Cox, Steve R. ; Thompson, Leslie ; Della-Coletta, Andrew A. ; Freimuth, William W. / Effect of food on the steady-state pharmacokinetics of delavirdine in patients with HIV infection. In: Clinical Drug Investigation. 2003 ; Vol. 23, No. 4. pp. 255-261.
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AU - Shelton, Mark J.

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AU - Thompson, Leslie

AU - Della-Coletta, Andrew A.

AU - Freimuth, William W.

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N2 - Objective: In a prior single-dose study that examined the effect of food on delavirdine pharmacokinetics in healthy volunteers, the absorption of delavirdine mesylate was delayed and the area under the curve was reduced by 26% in the presence of food. Since the complex, nonlinear pharmacokinetics of delavirdine do not permit a simple extrapolation of the results of a single-dose study to steady state, the present multiple-dose study was performed. Patients and study design: Thirteen stable patients with HIV-1 infection (two females, 11 males; CD4 count range 124-588 cells/mm3) completed a randomised, crossover study in which subjects received two 14-day treatments with delavirdine mesylate 400mg every 8 hours. In treatment A, all delavirdine doses were administered on an empty stomach and in treatment B were taken with food. A pharmacokinetic evaluation was performed on day 14 of each treatment period. Setting: An ambulatory AIDS research centre in an academic medical centre. Interventions: Administration of delavirdine with and without food. Main outcome measures: Pharmacokinetic parameters for delavirdine. Results: The maximum concentration (Cmax) [± standard deviation] in treatment A was 29.6 ± 13.6μM and in treatment B it was 23.0 ± 8.61μM (p = 0.037). The minimum concentrations (Cmin) were 9.45 ± 6.7μM and 11.2 ± 9.2μM, respectively (p > 0.05). The oral clearances (CLoral) were 17.8 ± 41.6 L/h (treatment A) and 18.5 ± 39.0 L/h (treatment B) [p > 0.05]. Similar patterns were observed for N-dealkylated delavirdine with a significant difference only in Cmax (4.13 vs 3.47μM [p = 0.022], treatment A vs B). Conclusions: These findings indicated that, in contrast to the increased CLoral noted in a prior single-dose study, food did not have a significant effect at steady state on the area under the plasma concentration-time curve or Cmin. Although Cmax was significantly lower when the drug was taken taken with food, the clinical relevance of this parameter as compared with the trough concentration is unclear since the current focus for antiretrovirals is on maintaining trough concentrations in excess of in vitro inhibitory concentrations.

AB - Objective: In a prior single-dose study that examined the effect of food on delavirdine pharmacokinetics in healthy volunteers, the absorption of delavirdine mesylate was delayed and the area under the curve was reduced by 26% in the presence of food. Since the complex, nonlinear pharmacokinetics of delavirdine do not permit a simple extrapolation of the results of a single-dose study to steady state, the present multiple-dose study was performed. Patients and study design: Thirteen stable patients with HIV-1 infection (two females, 11 males; CD4 count range 124-588 cells/mm3) completed a randomised, crossover study in which subjects received two 14-day treatments with delavirdine mesylate 400mg every 8 hours. In treatment A, all delavirdine doses were administered on an empty stomach and in treatment B were taken with food. A pharmacokinetic evaluation was performed on day 14 of each treatment period. Setting: An ambulatory AIDS research centre in an academic medical centre. Interventions: Administration of delavirdine with and without food. Main outcome measures: Pharmacokinetic parameters for delavirdine. Results: The maximum concentration (Cmax) [± standard deviation] in treatment A was 29.6 ± 13.6μM and in treatment B it was 23.0 ± 8.61μM (p = 0.037). The minimum concentrations (Cmin) were 9.45 ± 6.7μM and 11.2 ± 9.2μM, respectively (p > 0.05). The oral clearances (CLoral) were 17.8 ± 41.6 L/h (treatment A) and 18.5 ± 39.0 L/h (treatment B) [p > 0.05]. Similar patterns were observed for N-dealkylated delavirdine with a significant difference only in Cmax (4.13 vs 3.47μM [p = 0.022], treatment A vs B). Conclusions: These findings indicated that, in contrast to the increased CLoral noted in a prior single-dose study, food did not have a significant effect at steady state on the area under the plasma concentration-time curve or Cmin. Although Cmax was significantly lower when the drug was taken taken with food, the clinical relevance of this parameter as compared with the trough concentration is unclear since the current focus for antiretrovirals is on maintaining trough concentrations in excess of in vitro inhibitory concentrations.

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