Dose-dependent pharmacokinetics of delavirdine in combination with amprenavir in healthy volunteers

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

OBJECTIVES: To investigate different dose combinations of amprenavir and delavirdine in order to assess an optimal dose suitable for clinical use.

METHODS: This was a prospective, open-label, controlled, three-period, multiple-dose study with nine healthy volunteers. The volunteers received three different dose combinations of amprenavir and delavirdine twice a day for 10 days with a subsequent 12 h pharmacokinetic evaluation. Combination 1: amprenavir 600 mg and delavirdine 600 mg; combination 2: amprenavir 600 mg and delavirdine 800 mg; combination 3: amprenavir 450 mg and delavirdine 1000 mg. The combinations were taken at least 2 weeks apart.

RESULTS: Differences in median delavirdine Cmax, C12 and AUC0-12 were seen when comparing the three combinations (3 > 2>1) (P<0.04). A considerable and clinically important higher median C12 was seen with combination 3 when compared to combination 1 (835 to 3944 ng/mL) (P=0.0039). Only small differences in the amprenavir pharmacokinetic parameters were seen between the three dose combinations, with a median C12 of 412, 434 and 536 ng/mL, respectively.

CONCLUSIONS: In this study, an increase of 472% in median delavirdine C12 was seen with a delavirdine dose increase of only 67% (600 to 1000 mg). Saturation of the CYP3A4 enzymes and/or possibly also P-glycoprotein could be involved. Combination 3 was considered most suitable for clinical use, but because of the large inter-individual variation in steady-state concentrations, the use of the combination should be supported by therapeutic drug monitoring and restricted to certain patients.

OriginalsprogEngelsk
TidsskriftJournal of Antimicrobial Chemotherapy
Vol/bind54
Udgave nummer1
Sider (fra-til)206-210
ISSN0305-7453
DOI
StatusUdgivet - 2004

Fingeraftryk

Delavirdine
Pharmacokinetics
Cytochrome P-450 CYP3A
amprenavir
Drug Monitoring
P-Glycoprotein
Volunteers

Emneord

  • Adult
  • Anti-HIV Agents
  • Area Under Curve
  • Carbamates
  • Chromatography, High Pressure Liquid
  • Delavirdine
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Humans
  • Male
  • Prospective Studies
  • Spectrophotometry, Ultraviolet
  • Sulfonamides

Citer dette

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title = "Dose-dependent pharmacokinetics of delavirdine in combination with amprenavir in healthy volunteers",
abstract = "OBJECTIVES: To investigate different dose combinations of amprenavir and delavirdine in order to assess an optimal dose suitable for clinical use.METHODS: This was a prospective, open-label, controlled, three-period, multiple-dose study with nine healthy volunteers. The volunteers received three different dose combinations of amprenavir and delavirdine twice a day for 10 days with a subsequent 12 h pharmacokinetic evaluation. Combination 1: amprenavir 600 mg and delavirdine 600 mg; combination 2: amprenavir 600 mg and delavirdine 800 mg; combination 3: amprenavir 450 mg and delavirdine 1000 mg. The combinations were taken at least 2 weeks apart.RESULTS: Differences in median delavirdine Cmax, C12 and AUC0-12 were seen when comparing the three combinations (3 > 2>1) (P<0.04). A considerable and clinically important higher median C12 was seen with combination 3 when compared to combination 1 (835 to 3944 ng/mL) (P=0.0039). Only small differences in the amprenavir pharmacokinetic parameters were seen between the three dose combinations, with a median C12 of 412, 434 and 536 ng/mL, respectively.CONCLUSIONS: In this study, an increase of 472{\%} in median delavirdine C12 was seen with a delavirdine dose increase of only 67{\%} (600 to 1000 mg). Saturation of the CYP3A4 enzymes and/or possibly also P-glycoprotein could be involved. Combination 3 was considered most suitable for clinical use, but because of the large inter-individual variation in steady-state concentrations, the use of the combination should be supported by therapeutic drug monitoring and restricted to certain patients.",
keywords = "Adult, Anti-HIV Agents, Area Under Curve, Carbamates, Chromatography, High Pressure Liquid, Delavirdine, Dose-Response Relationship, Drug, Drug Combinations, Humans, Male, Prospective Studies, Spectrophotometry, Ultraviolet, Sulfonamides",
author = "Justesen, {Ulrik S} and Klitgaard, {Niels A} and Kim Brosen and Court Pedersen",
year = "2004",
doi = "10.1093/jac/dkh252",
language = "English",
volume = "54",
pages = "206--210",
journal = "Journal of Antimicrobial Chemotherapy",
issn = "0305-7453",
publisher = "Heinemann",
number = "1",

}

Dose-dependent pharmacokinetics of delavirdine in combination with amprenavir in healthy volunteers. / Justesen, Ulrik S; Klitgaard, Niels A; Brosen, Kim; Pedersen, Court.

I: Journal of Antimicrobial Chemotherapy, Bind 54, Nr. 1, 2004, s. 206-210.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Dose-dependent pharmacokinetics of delavirdine in combination with amprenavir in healthy volunteers

AU - Justesen, Ulrik S

AU - Klitgaard, Niels A

AU - Brosen, Kim

AU - Pedersen, Court

PY - 2004

Y1 - 2004

N2 - OBJECTIVES: To investigate different dose combinations of amprenavir and delavirdine in order to assess an optimal dose suitable for clinical use.METHODS: This was a prospective, open-label, controlled, three-period, multiple-dose study with nine healthy volunteers. The volunteers received three different dose combinations of amprenavir and delavirdine twice a day for 10 days with a subsequent 12 h pharmacokinetic evaluation. Combination 1: amprenavir 600 mg and delavirdine 600 mg; combination 2: amprenavir 600 mg and delavirdine 800 mg; combination 3: amprenavir 450 mg and delavirdine 1000 mg. The combinations were taken at least 2 weeks apart.RESULTS: Differences in median delavirdine Cmax, C12 and AUC0-12 were seen when comparing the three combinations (3 > 2>1) (P<0.04). A considerable and clinically important higher median C12 was seen with combination 3 when compared to combination 1 (835 to 3944 ng/mL) (P=0.0039). Only small differences in the amprenavir pharmacokinetic parameters were seen between the three dose combinations, with a median C12 of 412, 434 and 536 ng/mL, respectively.CONCLUSIONS: In this study, an increase of 472% in median delavirdine C12 was seen with a delavirdine dose increase of only 67% (600 to 1000 mg). Saturation of the CYP3A4 enzymes and/or possibly also P-glycoprotein could be involved. Combination 3 was considered most suitable for clinical use, but because of the large inter-individual variation in steady-state concentrations, the use of the combination should be supported by therapeutic drug monitoring and restricted to certain patients.

AB - OBJECTIVES: To investigate different dose combinations of amprenavir and delavirdine in order to assess an optimal dose suitable for clinical use.METHODS: This was a prospective, open-label, controlled, three-period, multiple-dose study with nine healthy volunteers. The volunteers received three different dose combinations of amprenavir and delavirdine twice a day for 10 days with a subsequent 12 h pharmacokinetic evaluation. Combination 1: amprenavir 600 mg and delavirdine 600 mg; combination 2: amprenavir 600 mg and delavirdine 800 mg; combination 3: amprenavir 450 mg and delavirdine 1000 mg. The combinations were taken at least 2 weeks apart.RESULTS: Differences in median delavirdine Cmax, C12 and AUC0-12 were seen when comparing the three combinations (3 > 2>1) (P<0.04). A considerable and clinically important higher median C12 was seen with combination 3 when compared to combination 1 (835 to 3944 ng/mL) (P=0.0039). Only small differences in the amprenavir pharmacokinetic parameters were seen between the three dose combinations, with a median C12 of 412, 434 and 536 ng/mL, respectively.CONCLUSIONS: In this study, an increase of 472% in median delavirdine C12 was seen with a delavirdine dose increase of only 67% (600 to 1000 mg). Saturation of the CYP3A4 enzymes and/or possibly also P-glycoprotein could be involved. Combination 3 was considered most suitable for clinical use, but because of the large inter-individual variation in steady-state concentrations, the use of the combination should be supported by therapeutic drug monitoring and restricted to certain patients.

KW - Adult

KW - Anti-HIV Agents

KW - Area Under Curve

KW - Carbamates

KW - Chromatography, High Pressure Liquid

KW - Delavirdine

KW - Dose-Response Relationship, Drug

KW - Drug Combinations

KW - Humans

KW - Male

KW - Prospective Studies

KW - Spectrophotometry, Ultraviolet

KW - Sulfonamides

U2 - 10.1093/jac/dkh252

DO - 10.1093/jac/dkh252

M3 - Journal article

VL - 54

SP - 206

EP - 210

JO - Journal of Antimicrobial Chemotherapy

JF - Journal of Antimicrobial Chemotherapy

SN - 0305-7453

IS - 1

ER -