Oxaliplatin Pharmacokinetics and Pharmacodynamics in Adult Cancer Patients with Impaired Renal Function
ABSTRACT To characterize the pharmacokinetics and pharmacodynamics of oxaliplatin in cancer patients with impaired renal function.
Thirty-four patients were stratified by 24-h urinary creatinine clearance (CrCL) into four renal dysfunction groups: group A (control, CrCL, >or=60 mL/min), B (mild, CrCL, 40-59 mL/min), C (moderate, CrCL, 20-39 mL/min), and D (severe, CrCL, <20 mL/min). Patients were treated with 60 to 130 mg/m2 oxaliplatin infused over 2 h every 3 weeks. Pharmacokinetic monitoring of platinum in plasma, plasma ultrafiltrates, and urine was done during cycles 1 and 2.
Plasma ultrafiltrate platinum clearance strongly correlated with CrCL (r2 = 0.712). Platinum elimination from plasma was triphasic, and maximal platinum concentrations (Cmax) were consistent across all renal impairment groups. However, only the beta-half-life was significantly prolonged by renal impairment, with values of 14.0 +/- 4.3, 20.3 +/- 17.7, 29.2 +/- 29.6, and 68.1 h in groups A, B, C, and D, respectively (P = 0.002). At a dose level of 130 mg/m2, the area under the concentration time curve increased in with the degree of renal impairment, with values of 16.4 +/- 5.03, 39.7 +/- 11.5, and 44.6 +/- 14.6 mug.h/mL, in groups A, B, and C, respectively. However, there was no increase in pharmacodynamic drug-related toxicities. Estimated CrCL using the Cockcroft-Gault method approximated the measured 24-h urinary CrCL (mean prediction error, -5.0 mL/min).
Oxaliplatin pharmacokinetics are altered in patients with renal impairment, but a corresponding increase in oxaliplatin-related toxicities is not observed.
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- "The fraction of plasma Pt recovered in the pUF was higher for oxaliplatin than for cisplatin, which could be a result of a higher reactivity of cisplatin and hence, a more extensive protein binding of cisplatin. Because pUF is generally considered to contain the pharmacologically active Pt fraction  and inactive species , the question arises as to whether ultrafiltrable Pt measured up to 75 months after chemotherapy is composed exclusively of inactive Pt bound to low-molecular-weight molecules smaller than 3 kDa, or whether it might also contain bound or unbound Pt with retained reactivity. Because ICP-MS can not distinguish between unchanged cisplatin/oxaliplatin and its metabolites or adducts, no information on the composition of the Pt species in the pUF samples could be obtained. "
ABSTRACT: The aim of this study was to evaluate long-term platinum retention in patients treated with cisplatin and oxaliplatin. 45 patients, treated 8-75 months before participating in this study, were included. Platinum levels in plasma and plasma ultrafiltrate (pUF) were determined. In addition, the reactivity of platinum species in pUF was evaluated. Relationships between platinum retention and possible determinants were evaluated. Platinum plasma concentrations ranged between 142-2.99 x 10(3) ng/L. Up to 24% of plasma platinum was recovered in pUF. No platinum-DNA adducts in peripheral blood mononuclear cells (PBMCs) could be detected. Ex vivo incubation of DNA with pUF of patients revealed that up to 10% of the reactivity of platinum species was retained. Protein binding proceeded during sample storage. Sodium thiosulfate (STS) appeared to release platinum from the plasma proteins. Platinum levels were related to time, dose, STS co-administration, and glomerular filtration rates (GFR). Our data suggest that plasma platinum levels are related to time, age, dose, GFR, and STS use. Platinum in plasma, probably, represent platinum eliminated from regenerating tissue. Platinum species in pUF were partly present in a reactive form. The effects of the reactivity on long-term consequences of Pt-containing chemotherapy, however, remains to be established.BMC Clinical Pharmacology 10/2008; 8:7. DOI:10.1186/1472-6904-8-7 · 1.36 Impact Factor
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ABSTRACT: In oncology, special populations are generally excluded from studies of investigational agents because dosing or scheduling information is limited or unknown. Patients who are members of special populations may be considered too frail to tolerate therapy. Special population study subjects may have hepatic or renal dysfunction from a variety of etiologies or may have poor performance status. Children and young adults represent another patient group with limited access to new agents. They are often excluded due to unique concerns about arresting or impeding their growth or development; their unique risks create an ethical dilemma in many cases. These populations are addressed in the following pages. This chapter’s emphasis is on ways to approach the study of special populations and on issues of greatest concern for investigators.
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