Population pharmacokinetics and pharmacodynamics of pegylated-liposomal doxorubicin in patients with AIDS-related Kaposi's sarcoma

Michael A. Amantea, Alan Forrest, Donald W Northfelt, Richard Mamelok

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

Objective: To characterize the population pharmacokinetics of pegylated-liposomal doxorubicin in patients with acquired immunodeficiency virus (AIDS)-related Kaposi's sarcoma and to explore the relationship between response of the cutaneous Kaposi's sarcoma lesions to treatment and measures of drug exposure. Methods: Forty-three male patients (median age, 40 years; age range, 28 to 50 years), body surface area, 1.89 m2; range, 1.5 to 2.3 m2) with AIDS and at least five biopsy-proved cutaneous Kaposi's sarcoma lesions were randomized to receive either a 10 or 20 mg/m2 dose of study drug for their first cycle and the alternate dose 3 weeks later. Patients continued to receive the study drug at a dose of 20 mg/m2 every 3 weeks. Serial blood samples were obtained after the first doses and analyzed by HPLC for determination of total plasma doxorubicin concentration. Kaposi's sarcoma lesion response was categorized as either progressive disease, stable disease, partial response, or complete response. Classification and regression tree (CART) analysis was used to determine the relationship between drug exposure and categorical lesion response. Iterative two-stage analysis was used to characterize both the pharmacokinetics of pegylated-liposomal doxorubicin and to model the probabilities of achieving a specific lesion response. Results: The pharmacokinetics of pegylated-liposomal doxorubicin were best described by a two-compartment linear structural model. Lesion response was significantly related to both the average daily maximum doxorubicin concentration (C(max,avg)) and dose intensity. Conclusions: The pharmacokinetics of pegylated-liposomal doxorubicin are strikingly different from conventional doxorubicin. Identification of both C(max,avg) and dose intensity as predictors of lesion response will provide guidelines for future dosing regimen designs.

Original languageEnglish (US)
Pages (from-to)301-311
Number of pages11
JournalClinical Pharmacology and Therapeutics
Volume61
Issue number3
DOIs
StatePublished - Mar 1997
Externally publishedYes

Fingerprint

Kaposi's Sarcoma
Pharmacokinetics
Doxorubicin
Viruses
Pharmaceutical Preparations
Population
Skin
Body Surface Area
Structural Models
Linear Models
High Pressure Liquid Chromatography
Regression Analysis
Guidelines
Biopsy
liposomal doxorubicin
Therapeutics

ASJC Scopus subject areas

  • Pharmacology

Cite this

Population pharmacokinetics and pharmacodynamics of pegylated-liposomal doxorubicin in patients with AIDS-related Kaposi's sarcoma. / Amantea, Michael A.; Forrest, Alan; Northfelt, Donald W; Mamelok, Richard.

In: Clinical Pharmacology and Therapeutics, Vol. 61, No. 3, 03.1997, p. 301-311.

Research output: Contribution to journalArticle

@article{84c9e1e9065d403da3a516d6c289dcad,
title = "Population pharmacokinetics and pharmacodynamics of pegylated-liposomal doxorubicin in patients with AIDS-related Kaposi's sarcoma",
abstract = "Objective: To characterize the population pharmacokinetics of pegylated-liposomal doxorubicin in patients with acquired immunodeficiency virus (AIDS)-related Kaposi's sarcoma and to explore the relationship between response of the cutaneous Kaposi's sarcoma lesions to treatment and measures of drug exposure. Methods: Forty-three male patients (median age, 40 years; age range, 28 to 50 years), body surface area, 1.89 m2; range, 1.5 to 2.3 m2) with AIDS and at least five biopsy-proved cutaneous Kaposi's sarcoma lesions were randomized to receive either a 10 or 20 mg/m2 dose of study drug for their first cycle and the alternate dose 3 weeks later. Patients continued to receive the study drug at a dose of 20 mg/m2 every 3 weeks. Serial blood samples were obtained after the first doses and analyzed by HPLC for determination of total plasma doxorubicin concentration. Kaposi's sarcoma lesion response was categorized as either progressive disease, stable disease, partial response, or complete response. Classification and regression tree (CART) analysis was used to determine the relationship between drug exposure and categorical lesion response. Iterative two-stage analysis was used to characterize both the pharmacokinetics of pegylated-liposomal doxorubicin and to model the probabilities of achieving a specific lesion response. Results: The pharmacokinetics of pegylated-liposomal doxorubicin were best described by a two-compartment linear structural model. Lesion response was significantly related to both the average daily maximum doxorubicin concentration (C(max,avg)) and dose intensity. Conclusions: The pharmacokinetics of pegylated-liposomal doxorubicin are strikingly different from conventional doxorubicin. Identification of both C(max,avg) and dose intensity as predictors of lesion response will provide guidelines for future dosing regimen designs.",
author = "Amantea, {Michael A.} and Alan Forrest and Northfelt, {Donald W} and Richard Mamelok",
year = "1997",
month = "3",
doi = "10.1016/S0009-9236(97)90162-4",
language = "English (US)",
volume = "61",
pages = "301--311",
journal = "Clinical Pharmacology and Therapeutics",
issn = "0009-9236",
publisher = "Nature Publishing Group",
number = "3",

}

TY - JOUR

T1 - Population pharmacokinetics and pharmacodynamics of pegylated-liposomal doxorubicin in patients with AIDS-related Kaposi's sarcoma

AU - Amantea, Michael A.

AU - Forrest, Alan

AU - Northfelt, Donald W

AU - Mamelok, Richard

PY - 1997/3

Y1 - 1997/3

N2 - Objective: To characterize the population pharmacokinetics of pegylated-liposomal doxorubicin in patients with acquired immunodeficiency virus (AIDS)-related Kaposi's sarcoma and to explore the relationship between response of the cutaneous Kaposi's sarcoma lesions to treatment and measures of drug exposure. Methods: Forty-three male patients (median age, 40 years; age range, 28 to 50 years), body surface area, 1.89 m2; range, 1.5 to 2.3 m2) with AIDS and at least five biopsy-proved cutaneous Kaposi's sarcoma lesions were randomized to receive either a 10 or 20 mg/m2 dose of study drug for their first cycle and the alternate dose 3 weeks later. Patients continued to receive the study drug at a dose of 20 mg/m2 every 3 weeks. Serial blood samples were obtained after the first doses and analyzed by HPLC for determination of total plasma doxorubicin concentration. Kaposi's sarcoma lesion response was categorized as either progressive disease, stable disease, partial response, or complete response. Classification and regression tree (CART) analysis was used to determine the relationship between drug exposure and categorical lesion response. Iterative two-stage analysis was used to characterize both the pharmacokinetics of pegylated-liposomal doxorubicin and to model the probabilities of achieving a specific lesion response. Results: The pharmacokinetics of pegylated-liposomal doxorubicin were best described by a two-compartment linear structural model. Lesion response was significantly related to both the average daily maximum doxorubicin concentration (C(max,avg)) and dose intensity. Conclusions: The pharmacokinetics of pegylated-liposomal doxorubicin are strikingly different from conventional doxorubicin. Identification of both C(max,avg) and dose intensity as predictors of lesion response will provide guidelines for future dosing regimen designs.

AB - Objective: To characterize the population pharmacokinetics of pegylated-liposomal doxorubicin in patients with acquired immunodeficiency virus (AIDS)-related Kaposi's sarcoma and to explore the relationship between response of the cutaneous Kaposi's sarcoma lesions to treatment and measures of drug exposure. Methods: Forty-three male patients (median age, 40 years; age range, 28 to 50 years), body surface area, 1.89 m2; range, 1.5 to 2.3 m2) with AIDS and at least five biopsy-proved cutaneous Kaposi's sarcoma lesions were randomized to receive either a 10 or 20 mg/m2 dose of study drug for their first cycle and the alternate dose 3 weeks later. Patients continued to receive the study drug at a dose of 20 mg/m2 every 3 weeks. Serial blood samples were obtained after the first doses and analyzed by HPLC for determination of total plasma doxorubicin concentration. Kaposi's sarcoma lesion response was categorized as either progressive disease, stable disease, partial response, or complete response. Classification and regression tree (CART) analysis was used to determine the relationship between drug exposure and categorical lesion response. Iterative two-stage analysis was used to characterize both the pharmacokinetics of pegylated-liposomal doxorubicin and to model the probabilities of achieving a specific lesion response. Results: The pharmacokinetics of pegylated-liposomal doxorubicin were best described by a two-compartment linear structural model. Lesion response was significantly related to both the average daily maximum doxorubicin concentration (C(max,avg)) and dose intensity. Conclusions: The pharmacokinetics of pegylated-liposomal doxorubicin are strikingly different from conventional doxorubicin. Identification of both C(max,avg) and dose intensity as predictors of lesion response will provide guidelines for future dosing regimen designs.

UR - http://www.scopus.com/inward/record.url?scp=0030898351&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030898351&partnerID=8YFLogxK

U2 - 10.1016/S0009-9236(97)90162-4

DO - 10.1016/S0009-9236(97)90162-4

M3 - Article

C2 - 9084455

AN - SCOPUS:0030898351

VL - 61

SP - 301

EP - 311

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

SN - 0009-9236

IS - 3

ER -