Clinical trials of modulation of multidrug resistance pharmacokinetic and pharmacodynamic considerations

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Abstract
A growing body of evidence indicates that expression of the mdr1 gene, which encodes the multidrug transporter, P-glycoprotein, contributes to chemotherapeutic resistance of human cancers. Expression of this protein in normal tissues such as the biliary tract, intestines, and renal tubules suggests a role in the excretion of toxins. Modulation of P-glycoprotein function in normal tissues may lead to decreased excretion of drugs and enhanced toxicities. A clinical trial of etoposide with escalating doses of cyclosporine (CsA) as a modulator of multidrug resistance was performed. CsA was delivered as a 2-hour loading dose followed by a 60-hour intravenous infusion, together with etoposide administered as a short infusion daily for 3 days. Patients received one or more courses of etoposide alone before the combined therapy to establish their clinical resistance to etoposide and to study etoposide pharmacokinetics without and then with CsA. Plasma and urinary etoposide was measured by high-performance liquid chromatography and plasma CsA by a nonspecific immunoassay. Conclusions from the initial phase I trial with the use of CsA as a modulator of etoposide are: (1) Serum CsA steady-state levels of up to 4800 ng/ml (4 microM) could be achieved with acceptable toxicity. (2) Toxicities caused by the combined treatment included increased nausea and vomiting, increased myelosuppression, and hyperbilirubinemia, consistent with modulation of P-glycoprotein function in the blood-brain barrier, hematopoietic stem cell, and biliary tract. Renal toxicity was uncommon, but severe in two patients with steady-state plasma CsA levels above 6000 ng/ml. (3) CsA administration had a marked effect on the pharmacokinetics of etoposide, with a doubling of the area under the concentration-time curve as a result of both decreased renal and nonrenal clearance, necessitating a 50% dose reduction in patients with normal renal function and hepatic function. (4) The recommended dose of CsA is a 6-7 mg/kg loading dose administered as a 2-hour intravenous infusion followed by a continuous infusion of 18-21 mg/kg/day for 60 hours with adjustments in the infusion rate to maintain steady-state serum levels of 3000-4800 ng/ml (2.5-4.0 M). We are performing additional phase I trials combining CsA with single-agent doxorubicin and taxol, and the CsA analog PSC-833 with various multidrug-resistant-related cytotoxins.