Toxicity of high-dose carboplatin: ultrafiltered and not total plasma pharmacokinetics is of clinical relevance.
Combination chemotherapy containing high-dose carboplatin is a therapeutic option for patients with poor-risk germ cell tumors. Since such treatment is relatively toxic, pharmacokinetic characteristics of total and ultrafiltered platinum, representing different species of platinum complexes formed, were investigated in 29 patients in relation to toxicity. The goodness-of-fit parameters revealed that a two-compartment model with weighting (1/C2i) resulted in the best fit. The terminal half-life of total platinum > 5 days was fourfold longer than that of ultrafiltered platinum, indicating long-term retention. At stem cell rescue, an ultrafiltered concentration of < or = 0.223 microg/ml did not impair hematological recovery. Ultrafiltered but not total platinum concentrations or AUC values were significantly correlated to an increase in creatinine concentration and different types of toxicity associated with high-dose treatment. Since the fraction unbound is time dependent and highly variable among patients, measuring ultrafiltered concentrations is highly recommended as they represent the clinically relevant platinum complexes in high-dose treatment.
Kloft
Charlotte
C
Department of Clinical Pharmacy, Freie Universitaet Berlin, Germany.
Siegert
Wolfgang
W
Beyer
Joerg
J
Jaehde
Ulrich
U
D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016190:Carboplatin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000008:administration & dosage; D018237:Germinoma / Q000378:metabolism / Q000628:therapy; D006207:Half-Life; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D013852:Thiotepa / Q000008:administration & dosage; D013997:Time Factors; D014462:Ultrafiltration
D000970:Antineoplastic Agents; D005047:Etoposide; D013852:Thiotepa; D016190:Carboplatin; D007069:Ifosfamide