Prochlorperazine as a doxorubicin-efflux blocker

phase I clinical and pharmacokinetics studies

K. S. Sridhar, A. Krishan, T. S A Samy, A. Sauerteig, L. L. Wellham, G. McPhee, R. C. Duncan, S. Y. Anac, Bach Ardalan, Pasquale W Benedetto

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Doxorubicin (DOX) efflux in drug-resistant cells is blocked by phenothiazines such as trifluoperazine (TFP) and prochlorperazine (PCZ) in vitro. The present phase I study was conducted in 13 patients with advanced, incurable, nonhematologic tumors to determine whether PCZ plasma levels high enough to block DOX efflux could be achieved in vivo. The treatment schedule consisted of prehydration and i. v. administration of 15, 30, 50, and 75 mg/m2 PCZ followed by a standard dose of 60 mg/m2 DOX. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose used. Toxicities attributable to PCZ were sedation, dryness of the mouth, cramps, chills, and restlessness. The maximal tolerated dose (MTD) of PCZ in this schedule was 75 mg/m2. Pharmacokinetic analysis indicated a large interpatient variation in peak plasma PCZ levels that ranged from 95 to 1100 ng/ml. The three plasma half-lives of PCZ were:t1/2α (±SE), 20.9±5.3 min;t1/2β, 1.8±0.3 h; and t1/2γ, 21.9±5.3 h. The volume of distribution (Vd), total clearance (ClT), and area under the curve (AUC) for PCZ were 2254±886 l/m2, 60.2±13.5 l m-2h-1, and 1624±686 ng ml-1 h, respectively. DOX retention in tumor cells retrieved from patients during the course of therapy indicated the appearance of cells with enhanced DOX retention. The combination of DOX and high-dose i. v. PCZ appeared to be safe, well tolerated, and active in non-small-cell lung carcinoma.

Original languageEnglish
Pages (from-to)423-430
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume31
Issue number6
DOIs
StatePublished - Nov 1 1993

Fingerprint

Prochlorperazine
Pharmacokinetics
Doxorubicin
Plasmas
Toxicity
Tumors
Appointments and Schedules
Cells
Clinical Studies
Phenothiazines
Muscle Cramp
Trifluoperazine
Xerostomia
Chills
Psychomotor Agitation
Maximum Tolerated Dose
Non-Small Cell Lung Carcinoma
Area Under Curve
Neoplasms

ASJC Scopus subject areas

  • Pharmacology
  • Oncology
  • Cancer Research

Cite this

Prochlorperazine as a doxorubicin-efflux blocker : phase I clinical and pharmacokinetics studies. / Sridhar, K. S.; Krishan, A.; Samy, T. S A; Sauerteig, A.; Wellham, L. L.; McPhee, G.; Duncan, R. C.; Anac, S. Y.; Ardalan, Bach; Benedetto, Pasquale W.

In: Cancer Chemotherapy and Pharmacology, Vol. 31, No. 6, 01.11.1993, p. 423-430.

Research output: Contribution to journalArticle

Sridhar, KS, Krishan, A, Samy, TSA, Sauerteig, A, Wellham, LL, McPhee, G, Duncan, RC, Anac, SY, Ardalan, B & Benedetto, PW 1993, 'Prochlorperazine as a doxorubicin-efflux blocker: phase I clinical and pharmacokinetics studies', Cancer Chemotherapy and Pharmacology, vol. 31, no. 6, pp. 423-430. https://doi.org/10.1007/BF00685030
Sridhar, K. S. ; Krishan, A. ; Samy, T. S A ; Sauerteig, A. ; Wellham, L. L. ; McPhee, G. ; Duncan, R. C. ; Anac, S. Y. ; Ardalan, Bach ; Benedetto, Pasquale W. / Prochlorperazine as a doxorubicin-efflux blocker : phase I clinical and pharmacokinetics studies. In: Cancer Chemotherapy and Pharmacology. 1993 ; Vol. 31, No. 6. pp. 423-430.
@article{768bf440d845489c9557bedd5289de0f,
title = "Prochlorperazine as a doxorubicin-efflux blocker: phase I clinical and pharmacokinetics studies",
abstract = "Doxorubicin (DOX) efflux in drug-resistant cells is blocked by phenothiazines such as trifluoperazine (TFP) and prochlorperazine (PCZ) in vitro. The present phase I study was conducted in 13 patients with advanced, incurable, nonhematologic tumors to determine whether PCZ plasma levels high enough to block DOX efflux could be achieved in vivo. The treatment schedule consisted of prehydration and i. v. administration of 15, 30, 50, and 75 mg/m2 PCZ followed by a standard dose of 60 mg/m2 DOX. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose used. Toxicities attributable to PCZ were sedation, dryness of the mouth, cramps, chills, and restlessness. The maximal tolerated dose (MTD) of PCZ in this schedule was 75 mg/m2. Pharmacokinetic analysis indicated a large interpatient variation in peak plasma PCZ levels that ranged from 95 to 1100 ng/ml. The three plasma half-lives of PCZ were:t1/2α (±SE), 20.9±5.3 min;t1/2β, 1.8±0.3 h; and t1/2γ, 21.9±5.3 h. The volume of distribution (Vd), total clearance (ClT), and area under the curve (AUC) for PCZ were 2254±886 l/m2, 60.2±13.5 l m-2h-1, and 1624±686 ng ml-1 h, respectively. DOX retention in tumor cells retrieved from patients during the course of therapy indicated the appearance of cells with enhanced DOX retention. The combination of DOX and high-dose i. v. PCZ appeared to be safe, well tolerated, and active in non-small-cell lung carcinoma.",
author = "Sridhar, {K. S.} and A. Krishan and Samy, {T. S A} and A. Sauerteig and Wellham, {L. L.} and G. McPhee and Duncan, {R. C.} and Anac, {S. Y.} and Bach Ardalan and Benedetto, {Pasquale W}",
year = "1993",
month = "11",
day = "1",
doi = "10.1007/BF00685030",
language = "English",
volume = "31",
pages = "423--430",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "6",

}

TY - JOUR

T1 - Prochlorperazine as a doxorubicin-efflux blocker

T2 - phase I clinical and pharmacokinetics studies

AU - Sridhar, K. S.

AU - Krishan, A.

AU - Samy, T. S A

AU - Sauerteig, A.

AU - Wellham, L. L.

AU - McPhee, G.

AU - Duncan, R. C.

AU - Anac, S. Y.

AU - Ardalan, Bach

AU - Benedetto, Pasquale W

PY - 1993/11/1

Y1 - 1993/11/1

N2 - Doxorubicin (DOX) efflux in drug-resistant cells is blocked by phenothiazines such as trifluoperazine (TFP) and prochlorperazine (PCZ) in vitro. The present phase I study was conducted in 13 patients with advanced, incurable, nonhematologic tumors to determine whether PCZ plasma levels high enough to block DOX efflux could be achieved in vivo. The treatment schedule consisted of prehydration and i. v. administration of 15, 30, 50, and 75 mg/m2 PCZ followed by a standard dose of 60 mg/m2 DOX. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose used. Toxicities attributable to PCZ were sedation, dryness of the mouth, cramps, chills, and restlessness. The maximal tolerated dose (MTD) of PCZ in this schedule was 75 mg/m2. Pharmacokinetic analysis indicated a large interpatient variation in peak plasma PCZ levels that ranged from 95 to 1100 ng/ml. The three plasma half-lives of PCZ were:t1/2α (±SE), 20.9±5.3 min;t1/2β, 1.8±0.3 h; and t1/2γ, 21.9±5.3 h. The volume of distribution (Vd), total clearance (ClT), and area under the curve (AUC) for PCZ were 2254±886 l/m2, 60.2±13.5 l m-2h-1, and 1624±686 ng ml-1 h, respectively. DOX retention in tumor cells retrieved from patients during the course of therapy indicated the appearance of cells with enhanced DOX retention. The combination of DOX and high-dose i. v. PCZ appeared to be safe, well tolerated, and active in non-small-cell lung carcinoma.

AB - Doxorubicin (DOX) efflux in drug-resistant cells is blocked by phenothiazines such as trifluoperazine (TFP) and prochlorperazine (PCZ) in vitro. The present phase I study was conducted in 13 patients with advanced, incurable, nonhematologic tumors to determine whether PCZ plasma levels high enough to block DOX efflux could be achieved in vivo. The treatment schedule consisted of prehydration and i. v. administration of 15, 30, 50, and 75 mg/m2 PCZ followed by a standard dose of 60 mg/m2 DOX. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose used. Toxicities attributable to PCZ were sedation, dryness of the mouth, cramps, chills, and restlessness. The maximal tolerated dose (MTD) of PCZ in this schedule was 75 mg/m2. Pharmacokinetic analysis indicated a large interpatient variation in peak plasma PCZ levels that ranged from 95 to 1100 ng/ml. The three plasma half-lives of PCZ were:t1/2α (±SE), 20.9±5.3 min;t1/2β, 1.8±0.3 h; and t1/2γ, 21.9±5.3 h. The volume of distribution (Vd), total clearance (ClT), and area under the curve (AUC) for PCZ were 2254±886 l/m2, 60.2±13.5 l m-2h-1, and 1624±686 ng ml-1 h, respectively. DOX retention in tumor cells retrieved from patients during the course of therapy indicated the appearance of cells with enhanced DOX retention. The combination of DOX and high-dose i. v. PCZ appeared to be safe, well tolerated, and active in non-small-cell lung carcinoma.

UR - http://www.scopus.com/inward/record.url?scp=0027408928&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027408928&partnerID=8YFLogxK

U2 - 10.1007/BF00685030

DO - 10.1007/BF00685030

M3 - Article

VL - 31

SP - 423

EP - 430

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 6

ER -