Effect of high-dose cyclosporine on etoposide pharmacodynamics in a trial to reverse P-glycoprotein (MDR1 gene) mediated drug resistance.
OBJECTIVE
The consequences of using cyclosporine (CsA) therapy to modulate P-glycoprotein-mediated multidrug resistance include increased myelosuppression, hyperbilirubinemia, and altered disposition of the cytotoxin. The purpose of this study was to analyze further the relationship between the degree of leukopenia, and etoposide pharmacokinetic factors.


METHODS
Each patient initially received intravenously-administered etoposide alone (150-200 mg/m2/d x 3). Later it was given in combination with CsA administered at escalating loading doses (range 2-7 mg/kg) as a 2 hour intravenous (IV) infusion followed by a 3 day continuous infusion, at doses ranging from 5 to 21 mg/ kg/day. Serial plasma etoposide concentration-time samples were assayed by high-performance liquid chromatography (HPLC). The area under the curve (AUC) of unbound etoposide was calculated from the total plasma etoposide AUC using a previous published equation [22] where % unbound etoposide = (1.4 x total bilirubin) - (6.8 x serum albumin) + 34.4. The percent decrease in white blood cell (WBC) count and the total or unbound etoposide AUC relationship was fitted to a sigmoid Emax model adapted for paired observations, where: % Decrease in WBC count =E(max) x PDRV(H+Z x delta)/(PDRV50 + Z x beta) + PDRVH + Z x delta In this equation, Z was the variable describing the two treatment groups (0 = no CsA and 1 = CsA). The fitted parameters were PDRV50, the pharmacodynamic response variable (PDRV) producing 50% of the maximal response; parameter beta, which describes the effect of the treatment group on the PDRV50; parameter H (Hill constant), which defines the slope of the response curve and parameter delta, which describes the effect of the treatment group on parameter H.


RESULTS
CsA at a median concentration of 1,938 microg/ml resulted in a median increase in the total plasma etoposide AUC by 103% and the calculated unbound plasma etoposide AUC by 104%. This paralleled a 12% greater median percent decrease in WBC count during etoposide + CsA treatment (72% vs. 84%, P = 0.03). The percent decrease in WBC count and total or unbound etoposide AUC relationship was fitted to the sigmoid Emax model. The model using the unbound etoposide AUC described the data adequately (r = 0.790) and was precise, with a mean absolute error of 6.4% (95% confidence interval: -4.9, 7.8). The fitted parameter-estimates suggested that at equivalent unbound etoposide AUC values above 10 microg x h/ml, the sigmoid Emax model predicted a 5% greater WBC count suppression when CsA was added to the treatment regimen.


CONCLUSIONS
These findings suggest that a small degree of the enhanced myelosuppression observed with CsA combined with etoposide might be attributable to inhibition of P-glycoprotein in bone marrow precursor cells. However, the majority of the effect observed appears to be due to pharmacokinetic interactions, which result in increases in unbound etoposide.
Lum
B L
BL
Clinical Cancer Center at Stanford Hospitals and Clinics, California 94305, USA. bert.lum@stanford.edu
Kaubisch
S
S
Fisher
G A
GA
Brown
B W
BW
Sikic
B I
BI
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001855:Bone Marrow Diseases / Q000097:blood / Q000139:chemically induced; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D015672:Erythroid Precursor Cells / Q000187:drug effects; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D019450:Genes, MDR / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007262:Infusions, Intravenous; D007958:Leukocyte Count / Q000187:drug effects; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged
D000972:Antineoplastic Agents, Phytogenic; D007166:Immunosuppressive Agents; D005047:Etoposide; D016572:Cyclosporine