Single-dose pharmacokinetics of delavirdine mesylate and didanosine in patients with human immunodeficiency virus infection

G. D. Morse, Margaret A Fischl, M. J. Shelton, S. R. Cox, M. Driver, M. Deremer, W. W. Freimuth

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Delavirdine is a nonnucleoside reverse transcriptase inhibitor with in vitro activity against human immunodeficiency virus type 1 (HIV-1) that is currently being evaluated in combination regimens with various nucleoside analogs, including didanosine. Due to the pH-dependent solubility of delavirdine, the buffering agents in didanosine formulations may reduce delavirdine absorption. To evaluate the potential interaction between these agents, 12 HIV-infected patients (mean [± standard deviation] CD4+ cell count, 304 ± 213/mm3) were enrolled in a three-way crossover single-dose study. Didanosine (125 to 200 mg given as buffered tablets) and delavirdine mesylate (400 mg) pharmacokinetics were evaluated when each drug was given alone (treatments A and B, respectively), when the two drugs were given concurrently (treatment C), and when didanosine was given 1 h after delavirdine (treatment D). Delavirdine exposure was reduced by concurrent administration of didanosine. The maximum drug concentration in serum (C(max)) was reduced from 7.22 ± 4.0 to 3.51 ± 1.9 μM, and the area under the concentration-time curve from 0 h to infinity (AUC(0→∞)) was reduced from 22.5 ± 14 to 14 ± 5.7 μM γ h. The extent of N-dealkylation, as indicated by the ratio of the N-dealkylated delavirdine AUC(0→∞) to the delavirdine AUC(0→∞), was unchanged across study treatments (P = 0.708). Reductions in didanosine exposure were observed during concurrent administration with delavirdine with a C(max) reduction from 4.65 ± 2.0 to 3.22 ± 0.59 μM and an AUC(0→∞) reduction from 7.93 ± 3.9 to 6.54 ± 2.3 μM · h. Thus, concurrent administration of delavirdine and didanosine may reduce the AUC(0→∞) of both drugs, although the clinical significance of this reduction is unknown. Administration of delavirdine 1 h before didanosine avoided the interaction. Due to the single-dose nature of this study, these findings require further evaluation at steady state.

Original languageEnglish
Pages (from-to)169-174
Number of pages6
JournalAntimicrobial Agents and Chemotherapy
Volume41
Issue number1
StatePublished - Jan 7 1997
Externally publishedYes

Fingerprint

Delavirdine
Didanosine
Virus Diseases
Pharmacokinetics
HIV
Area Under Curve
Pharmaceutical Preparations
Dealkylation
Reverse Transcriptase Inhibitors
Therapeutics
CD4 Lymphocyte Count
Nucleosides
Solubility
Tablets

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Single-dose pharmacokinetics of delavirdine mesylate and didanosine in patients with human immunodeficiency virus infection. / Morse, G. D.; Fischl, Margaret A; Shelton, M. J.; Cox, S. R.; Driver, M.; Deremer, M.; Freimuth, W. W.

In: Antimicrobial Agents and Chemotherapy, Vol. 41, No. 1, 07.01.1997, p. 169-174.

Research output: Contribution to journalArticle

Morse, G. D. ; Fischl, Margaret A ; Shelton, M. J. ; Cox, S. R. ; Driver, M. ; Deremer, M. ; Freimuth, W. W. / Single-dose pharmacokinetics of delavirdine mesylate and didanosine in patients with human immunodeficiency virus infection. In: Antimicrobial Agents and Chemotherapy. 1997 ; Vol. 41, No. 1. pp. 169-174.
@article{5c3474ac6262477288948034a9dfa2cd,
title = "Single-dose pharmacokinetics of delavirdine mesylate and didanosine in patients with human immunodeficiency virus infection",
abstract = "Delavirdine is a nonnucleoside reverse transcriptase inhibitor with in vitro activity against human immunodeficiency virus type 1 (HIV-1) that is currently being evaluated in combination regimens with various nucleoside analogs, including didanosine. Due to the pH-dependent solubility of delavirdine, the buffering agents in didanosine formulations may reduce delavirdine absorption. To evaluate the potential interaction between these agents, 12 HIV-infected patients (mean [± standard deviation] CD4+ cell count, 304 ± 213/mm3) were enrolled in a three-way crossover single-dose study. Didanosine (125 to 200 mg given as buffered tablets) and delavirdine mesylate (400 mg) pharmacokinetics were evaluated when each drug was given alone (treatments A and B, respectively), when the two drugs were given concurrently (treatment C), and when didanosine was given 1 h after delavirdine (treatment D). Delavirdine exposure was reduced by concurrent administration of didanosine. The maximum drug concentration in serum (C(max)) was reduced from 7.22 ± 4.0 to 3.51 ± 1.9 μM, and the area under the concentration-time curve from 0 h to infinity (AUC(0→∞)) was reduced from 22.5 ± 14 to 14 ± 5.7 μM γ h. The extent of N-dealkylation, as indicated by the ratio of the N-dealkylated delavirdine AUC(0→∞) to the delavirdine AUC(0→∞), was unchanged across study treatments (P = 0.708). Reductions in didanosine exposure were observed during concurrent administration with delavirdine with a C(max) reduction from 4.65 ± 2.0 to 3.22 ± 0.59 μM and an AUC(0→∞) reduction from 7.93 ± 3.9 to 6.54 ± 2.3 μM · h. Thus, concurrent administration of delavirdine and didanosine may reduce the AUC(0→∞) of both drugs, although the clinical significance of this reduction is unknown. Administration of delavirdine 1 h before didanosine avoided the interaction. Due to the single-dose nature of this study, these findings require further evaluation at steady state.",
author = "Morse, {G. D.} and Fischl, {Margaret A} and Shelton, {M. J.} and Cox, {S. R.} and M. Driver and M. Deremer and Freimuth, {W. W.}",
year = "1997",
month = "1",
day = "7",
language = "English",
volume = "41",
pages = "169--174",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "1",

}

TY - JOUR

T1 - Single-dose pharmacokinetics of delavirdine mesylate and didanosine in patients with human immunodeficiency virus infection

AU - Morse, G. D.

AU - Fischl, Margaret A

AU - Shelton, M. J.

AU - Cox, S. R.

AU - Driver, M.

AU - Deremer, M.

AU - Freimuth, W. W.

PY - 1997/1/7

Y1 - 1997/1/7

N2 - Delavirdine is a nonnucleoside reverse transcriptase inhibitor with in vitro activity against human immunodeficiency virus type 1 (HIV-1) that is currently being evaluated in combination regimens with various nucleoside analogs, including didanosine. Due to the pH-dependent solubility of delavirdine, the buffering agents in didanosine formulations may reduce delavirdine absorption. To evaluate the potential interaction between these agents, 12 HIV-infected patients (mean [± standard deviation] CD4+ cell count, 304 ± 213/mm3) were enrolled in a three-way crossover single-dose study. Didanosine (125 to 200 mg given as buffered tablets) and delavirdine mesylate (400 mg) pharmacokinetics were evaluated when each drug was given alone (treatments A and B, respectively), when the two drugs were given concurrently (treatment C), and when didanosine was given 1 h after delavirdine (treatment D). Delavirdine exposure was reduced by concurrent administration of didanosine. The maximum drug concentration in serum (C(max)) was reduced from 7.22 ± 4.0 to 3.51 ± 1.9 μM, and the area under the concentration-time curve from 0 h to infinity (AUC(0→∞)) was reduced from 22.5 ± 14 to 14 ± 5.7 μM γ h. The extent of N-dealkylation, as indicated by the ratio of the N-dealkylated delavirdine AUC(0→∞) to the delavirdine AUC(0→∞), was unchanged across study treatments (P = 0.708). Reductions in didanosine exposure were observed during concurrent administration with delavirdine with a C(max) reduction from 4.65 ± 2.0 to 3.22 ± 0.59 μM and an AUC(0→∞) reduction from 7.93 ± 3.9 to 6.54 ± 2.3 μM · h. Thus, concurrent administration of delavirdine and didanosine may reduce the AUC(0→∞) of both drugs, although the clinical significance of this reduction is unknown. Administration of delavirdine 1 h before didanosine avoided the interaction. Due to the single-dose nature of this study, these findings require further evaluation at steady state.

AB - Delavirdine is a nonnucleoside reverse transcriptase inhibitor with in vitro activity against human immunodeficiency virus type 1 (HIV-1) that is currently being evaluated in combination regimens with various nucleoside analogs, including didanosine. Due to the pH-dependent solubility of delavirdine, the buffering agents in didanosine formulations may reduce delavirdine absorption. To evaluate the potential interaction between these agents, 12 HIV-infected patients (mean [± standard deviation] CD4+ cell count, 304 ± 213/mm3) were enrolled in a three-way crossover single-dose study. Didanosine (125 to 200 mg given as buffered tablets) and delavirdine mesylate (400 mg) pharmacokinetics were evaluated when each drug was given alone (treatments A and B, respectively), when the two drugs were given concurrently (treatment C), and when didanosine was given 1 h after delavirdine (treatment D). Delavirdine exposure was reduced by concurrent administration of didanosine. The maximum drug concentration in serum (C(max)) was reduced from 7.22 ± 4.0 to 3.51 ± 1.9 μM, and the area under the concentration-time curve from 0 h to infinity (AUC(0→∞)) was reduced from 22.5 ± 14 to 14 ± 5.7 μM γ h. The extent of N-dealkylation, as indicated by the ratio of the N-dealkylated delavirdine AUC(0→∞) to the delavirdine AUC(0→∞), was unchanged across study treatments (P = 0.708). Reductions in didanosine exposure were observed during concurrent administration with delavirdine with a C(max) reduction from 4.65 ± 2.0 to 3.22 ± 0.59 μM and an AUC(0→∞) reduction from 7.93 ± 3.9 to 6.54 ± 2.3 μM · h. Thus, concurrent administration of delavirdine and didanosine may reduce the AUC(0→∞) of both drugs, although the clinical significance of this reduction is unknown. Administration of delavirdine 1 h before didanosine avoided the interaction. Due to the single-dose nature of this study, these findings require further evaluation at steady state.

UR - http://www.scopus.com/inward/record.url?scp=0031020802&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031020802&partnerID=8YFLogxK

M3 - Article

C2 - 8980774

AN - SCOPUS:0031020802

VL - 41

SP - 169

EP - 174

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 1

ER -