title: Alteration of etoposide pharmacokinetics and pharmacodynamics by cyclosporine in a phase I trial to modulate multidrug resistance.
abstract: OBJECTIVE
  To determine the effects of high-dose cyclosporine (CsA) infusion on the pharmacokinetics of etoposide in patients with cancer.
  
  
  METHODS
  Sixteen patients were administered 20 paired courses of etoposide and CsA/etoposide. Etoposide was administered daily for three days, alone or with CsA, which was delivered by a loading dose and 3-day infusion. Etoposide was measured by high-performance liquid chromatography (HPLC) and serum CsA by nonspecific immunoassay. Etoposide pharmacokinetics included area under the concentration-time curve (AUC), total and renal clearance (CL), half-life (T1/2), and volume of distribution at steady state (Vss).
  
  
  RESULTS
  CsA concentrations more than 2,000 ng/mL produced an increase in etoposide AUC of 80% (P less than .001), a 38% decrease in total CL (P < .01), a > twofold increase in T1/2 (P < .01), and a 46% larger Vss (P = .01) compared with etoposide alone. CsA levels ranged from 297 to 5,073 ng/mL. Higher CsA levels (< 2,000 ng/mL v > 2,000 ng/mL) resulted in greater changes in etoposide kinetics: Vss (1.4% v 46%) and T1/2 (40% v 108%). CsA produced a 38% decrease in renal and a 52% decrease in nonrenal CL of etoposide. Etoposide with CsA levels > 2,000 ng/mL produced a lower WBC count nadir (900/mm3 v 1,600/mm3) compared with baseline etoposide cycles.
  
  
  CONCLUSIONS
  High-dose CsA produces significant increases in etoposide systemic exposure and leukopenia. These pharmacokinetic changes are consistent with inhibition by CsA of the multidrug transporter P-glycoprotein in normal tissues. Etoposide doses should be reduced by 50% when used with high-dose CsA in patients with normal renal and liver function. Alterations in the disposition of other multidrug resistance (MDR)-related drugs should be expected to occur with modulation of P-glycoprotein function in clinical trials.
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Palo Alto, CA.
authors.forename: B L
authors.initials: BL
authors.lastname: Lum
authors.forename: S
authors.initials: S
authors.lastname: Kaubisch
authors.forename: A M
authors.initials: AM
authors.lastname: Yahanda
authors.forename: K M
authors.initials: KM
authors.lastname: Adler
authors.forename: L
authors.initials: L
authors.lastname: Jew
authors.forename: M N
authors.initials: MN
authors.lastname: Ehsan
authors.forename: N A
authors.initials: NA
authors.lastname: Brophy
authors.forename: J
authors.initials: J
authors.lastname: Halsey
authors.forename: M P
authors.initials: MP
authors.lastname: Gosland
authors.forename: B I
authors.initials: BI
authors.lastname: Sikic
mesh_terms: D000328:Adult; D000368:Aged; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology*; D004347:Drug Interactions; D004351:Drug Resistance; D005047:Etoposide / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D005047:Etoposide; D016572:Cyclosporine