Preclinical toxicity and pharmacology of liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II)

Roman Perez-Soler, J. Lautersztain, L. C. Stephens, K. Wright, A. R. Khokhar

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Liposome-entrapped cis-bis-neodecanoate-trans-R,R-1,2-diaminocylohexane platinum(II) (L-NDDP) is a new lipophilic cisplatin derivative formulated in a liposomal carrier currently in phase I clinical trials. The preclinical toxicity and pharmacology of L-NDDP were studied in mice and dogs. At the LD50 dose (i.v. bolus) in mice (60.5 mg/kg or 181.5 mg/m2), a tenfold decrease in the granulocyte and platelet counts was observed in the absence of renal toxic effects. In dogs, the maximum tolerated dose (MTD) of L-NDDP given i.v. over a period of 45-60 min was 150 mg/m2. This dose produced significant vomiting (6-18 episodes), minimal renal dysfunction, a maximal decrease in granulocyte and platelet counts of from 30% to 70%, and acute and transient elevation of liver enzymes. Higher doses (225 and 300 mg/m2) resulted in severe gastrointestinal (GI) toxicity in one animal and the death of two others within 48 h. Autopsy results showed multifocal hemorrhages in the lungs, GI tract, kidney, and liver. Three dogs were treated monthly with the MTD up to a cumulative dose of 637.5-712.5 mg/m2 with excellent tolerance. No cumulative myelosuppression or liver dysfunction was observed, whereas a slight increase in the creatinine baseline level was detected in all three animals. Autopsy results at the end of the study showed mild changes limited to the liver, kidney, and GI tract. Pharmacologic studies showed that the drug was cleared, fitting a two-compartment model with a mean t1/2α of 7.1 min and a t1/2β of 87.8 h. These studies show that L-NDDP can safely be given at therapeutic doses to animals and that the dose-limiting toxic effects consists of myelosuppression in mice and a multiorgan hemorrhagic syndrome related to vascular injury in dogs.

Original languageEnglish (US)
Pages (from-to)1-8
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume24
Issue number1
DOIs
StatePublished - Jul 1989
Externally publishedYes

Fingerprint

Liposomes
Liver
Toxicity
Pharmacology
Dogs
Kidney
Animals
Maximum Tolerated Dose
Poisons
Platelets
Platelet Count
Granulocytes
Gastrointestinal Tract
Autopsy
Clinical Trials, Phase I
Vascular System Injuries
Lethal Dose 50
Platinum
Cisplatin
Vomiting

ASJC Scopus subject areas

  • Pharmacology
  • Oncology
  • Cancer Research

Cite this

Preclinical toxicity and pharmacology of liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II). / Perez-Soler, Roman; Lautersztain, J.; Stephens, L. C.; Wright, K.; Khokhar, A. R.

In: Cancer Chemotherapy and Pharmacology, Vol. 24, No. 1, 07.1989, p. 1-8.

Research output: Contribution to journalArticle

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abstract = "Liposome-entrapped cis-bis-neodecanoate-trans-R,R-1,2-diaminocylohexane platinum(II) (L-NDDP) is a new lipophilic cisplatin derivative formulated in a liposomal carrier currently in phase I clinical trials. The preclinical toxicity and pharmacology of L-NDDP were studied in mice and dogs. At the LD50 dose (i.v. bolus) in mice (60.5 mg/kg or 181.5 mg/m2), a tenfold decrease in the granulocyte and platelet counts was observed in the absence of renal toxic effects. In dogs, the maximum tolerated dose (MTD) of L-NDDP given i.v. over a period of 45-60 min was 150 mg/m2. This dose produced significant vomiting (6-18 episodes), minimal renal dysfunction, a maximal decrease in granulocyte and platelet counts of from 30{\%} to 70{\%}, and acute and transient elevation of liver enzymes. Higher doses (225 and 300 mg/m2) resulted in severe gastrointestinal (GI) toxicity in one animal and the death of two others within 48 h. Autopsy results showed multifocal hemorrhages in the lungs, GI tract, kidney, and liver. Three dogs were treated monthly with the MTD up to a cumulative dose of 637.5-712.5 mg/m2 with excellent tolerance. No cumulative myelosuppression or liver dysfunction was observed, whereas a slight increase in the creatinine baseline level was detected in all three animals. Autopsy results at the end of the study showed mild changes limited to the liver, kidney, and GI tract. Pharmacologic studies showed that the drug was cleared, fitting a two-compartment model with a mean t1/2α of 7.1 min and a t1/2β of 87.8 h. These studies show that L-NDDP can safely be given at therapeutic doses to animals and that the dose-limiting toxic effects consists of myelosuppression in mice and a multiorgan hemorrhagic syndrome related to vascular injury in dogs.",
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