A dosage formula has been derived from a retrospective analysis of carboplatin pharmacokinetics in 18 patients with pretreatment glomerular filtration rates (GFR) in the range of 33 to 136 mL/min. Carboplatin plasma clearance was linearly related to GFR (r = 0.85, P less than .00001) and rearrangements of the equation describing the correlation gave the dosage formula dose (mg) = target area under the free carboplatin plasma concentration versus time curve (AUC) x (1.2 x GFR + 20). In a prospective clinical and pharmacokinetic study the formula was used to determine the dose required to treat 31 patients (GFR range, 33 to 135 mL/min) with 40 courses of carboplatin. The target AUC was escalated from 3 to 8 mg carboplatin/mL/min. Over this AUC range the formula accurately predicted the observed AUC (observed/predicted ratio 1.24 +/- 0.11, r = 0.886) and using these additional data, the formula was refined. Dose (mg) = target AUC x (GFR + 25) is now the recommended formula. AUC values of 4 to 6 and 6 to 8 mg/mL. min gave rise to manageable hematological toxicity in previously treated and untreated patients, respectively, and hence target AUC values of 5 and 7 mg/mL min are recommended for single-agent carboplatin in these patient groups. Pharmacokinetic modeling demonstrated that the formula was reasonably accurate regardless of whether a one- or two-compartment model most accurately described carboplatin pharmacokinetics, assuming that body size did not influence nonrenal clearance. The validity of this assumption was demonstrated in 13 patients where no correlation between surface area and nonrenal clearance was found (r = .31, P = .30). Therefore, the formula provides a simple and consistent method of determining carboplatin dose in adults. Since the measure of carboplatin exposure in the formula is AUC, and not toxicity, it will not be influenced by previous or concurrent myelosuppressive therapy or supportive measures. The formula is therefore applicable to combination and high-dose studies as well as conventional single-agent therapy, although the target AUC for carboplatin will need to be redefined for combination chemotherapy.

Carboplatin dosage: prospective evaluation of a simple formula based on renal function.

PURPOSESerious cumulative toxicity is a well-recognized consequence of chemotherapy. Amifostine, an organic thiophosphate, has demonstrated the ability to protect selectively a broad range of normal, but not neoplastic, tissues from the cytotoxic effects of chemotherapy and radiotherapy. This study was designed to determine if amifostine could reduce the serious toxicities associated with cyclophosphamide and cisplatin (CP), without reducing antitumor efficacy in patients with ovarian cancer.PATIENTS AND METHODSTwo hundred forty-two patients with advanced ovarian cancer were randomized to receive six cycles of cyclophosphamide (1,000 mg/m2) and cisplatin (100 mg/m2) with or without amifostine (910 mg/m2) every 3 weeks for six cycles. The occurrence of hematologic, renal, neurologic, and ototoxicity was evaluated. Antitumor efficacy was assessed by pathologic tumor response and survival.RESULTSPretreatment with amifostine before each cycle of chemotherapy resulted in a reduction of cumulative toxicities. H...

Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer.

PURPOSETo review the current dose-calculation practice and propose a non-body-surface area (BSA)-based dose-calculation method.METHODSData that supported the introduction of BSA-based dose calculation in the late 1950s were reviewed. Data on 18 drugs that correlated pharmacokinetic (PK) variables for cytotoxic drugs with BSA were examined. Other methods of dose calculation, such as therapeutic drug monitoring (TDM) and adaptive control, were also examined.RESULTSThe BSA-based method of dose calculation was adopted without adequate investigation of its accuracy. BSA fails to standardize the marked interpatient variation in PK for most cytotoxic drugs. A definite correlation was found between PK variables and BSA for only one drug (docetaxel). PK parameters correlate with toxicity, as well as response in some tumors, but do not completely explain the variation in drug effect between individuals. The complexities of TDM may make its universal use impractical. A non-BSA-based dose calculation method is propos...

Dose calculation of anticancer drugs: a review of the current practice and introduction of an alternative.

Since the discovery of the biologically active platinum complexes 30 years ago, 2 agents have become widely established in clinical oncology practice. Both cisplatin and carboplatin are platinum(II) complexes with 2 ammonia groups in the cis- position. However, they differ in their solubility, chemical reactivity, dichloride or alicyclic oxygenated leaving groups, pharmacokinetics and toxicology. Cisplatin causes severe renal tubular damage and reduces glomerular filtration, and requires concurrent saline hydration and mannitol diuresis to eliminate potentially lethal and unacceptable damage to the kidneys. Carboplatin, at conventional doses, causes no decrease in glomerular filtration and only minor transient elevations in urinary enzymes. Cisplatin is the most emetic cancer drug in common use, while nausea and vomiting associated with carboplatin are moderately severe. Serotonin release from enterochromaffin gut mucosal cells and stimulation of serotonin 5-HT3-receptors mediates acute emesis. Selective inhibitors of the 5-HT3-receptor protect against cisplatin- and carboplatin-induced nausea and vomiting. Peripheral neurotoxicity is the most dose-limiting problem associated with cisplatin. Loss of vibration sense, paraesthesia and sensory ataxia comes on after several treatment cycles. Carboplatin, however, is relatively free from peripheral neurotoxicity. Audiometry shows cisplatin-induced ototoxicity in 75 to 100% of patients, which may be associated with tinnitus and hearing loss. Ototoxicity is rare with conventional dose carboplatin therapy. Monitoring hearing with audiograms may identify early signs before significant impairment occurs. Cisplatin causes mild haematological toxicity to all 3 blood lineages. Haematological toxicity is dose-limiting for carboplatin, with thrombocytopenia being a greater problem than leucopenia. Although carboplatin is not toxic to the kidney, renal function markedly affects the severity of carboplatin-induced thrombocytopenia. The major clearance mechanism of cisplatin is irreversible binding in plasma and tissues, while carboplatin is cleared by glomerular filtration. Metabolism of cisplatin to aqua, amino acid and protein species is extensive, whereas carboplatin exists mainly as the free unchanged form. Strong relationships between carboplatin renal clearance, glomerular filtration rate, area under the plasma concentration-time curve (AUC) of filterable platinum and severity of thrombocytopenia have prompted dose adjustment according to renal function. New analogues such as JM216 offer the potential advantages of oral administration and few nonhaematological toxicities. Analogues based on the diaminocyclohexane ligand have encountered problematic neurotoxicity.

Comparative Adverse Effect Profiles of Platinum Drugs

The translation of advances in cancer biology to drug discovery can be complicated by pharmacokinetic variation between individuals and within individuals, and this can result in unpredictable toxicity and variable antineoplastic effects. Previously unrecognized variables (such as genetic polymorphisms) are now known to have a significant impact on drug disposition. How can the pharmacokinetic variability of anticancer agents be reduced? This will require the understanding of correlations between pharmacokinetics and treatment outcomes, the identification of relevant patient parameters, mathematical modelling of individual and population pharmacokinetics, and the development of algorithms that will tailor doses to the individual patient.

Pharmacokinetic variability of anticancer agents

We previously correlated both renal function and thrombocytopenia, the dose limiting toxicity of carboplatin, with the plasma pharmacokinetics of carboplatin. From these correlations, we developed equations to calculate carboplatin dosage for any patient based on that patient9s creatinine clearance, body surface area, pretreatment platelet count, desired platelet nadir, and status of prior chemotherapy. We prospectively applied these equations in 44 courses of carboplatin given to 24 patients. There were 13 males and 11 females with median age 53 (range, 33–77), median Karnofsky performance status 80 (range, 50–100), and creatinine clearance 32 to 118 ml/min. Ten patients had creatinine clearances less than 60 ml/min. Precision of the equations used for dose calculation was evaluable in 38 courses administered to 23 patients. In 23 courses of carboplatin administered to 12 patients without extensive prior chemotherapy, the observed change in platelets = 1.04 × predicted change - 48,000 ( r = 0.96). In the 15 courses of carboplatin administered to 11 heavily pretreated patients, the observed change in platelets = 1.13 × predicted change + 6,600 ( r = 0.97). For the overall combined population, the observed change in platelets = 0.96 × predicted change - 7,000 ( r = 0.94). These relationships which nearly define the line of identity (observed = expected) validate our initial observations. Only 2 patients developed WBC

Prospective validation of a pharmacologically based dosing scheme for the cis-diamminedichloroplatinum(II) analogue diamminecyclobutanedicarboxylatoplatinum.

The plasma pharmacokinetics and tissue distribution of dimethyl sulfoxide in mice.

We have investigated the metabolism and disposition, in mice, of 7-con-O-methylnogarol ( menogarol ; 7-OMEN), a new anthracycline antibiotic entering clinical trials. 7-OMEN, dissolved in 0.01 M glucuronic acid, was administered iv to mice (10 mg/kg). At specified times after injection, groups of mice were killed and 7-OMEN and metabolites were assayed in plasma and organs by HPLC. Plasma concentrations of 7-OMEN declined in triexponential fashion. The terminal t1/2 was 10.6 hr; the AUC was 10.13 microM X hr; the apparent Vc was 0.4 liter/m2, and the systemic clearance was 91.2 ml/min/m2. One metabolite, with the same HPLC characteristics as N- demethylmenogarol , was seen in plasma during the first 30 min after injection. 7-OMEN was distributed extensively to all tissues except brain. Initially, pulmonary concentrations of 7-OMEN were 15 times higher than those in any other organ and 30 times higher than those in plasma. Concentrations of 7-OMEN were the most persistent in spleen, kidney, and pancreas, and the least persistent in heart and liver. The AUC for 7-OMEN in organs was the greatest in lungs (605 nmol/g X hr), spleen (522 nmol/g X hr), and pancreas (430 nmol/g X hr), and least in heart (33 nmol/g X hr) and liver (60 nmol/g X hr). Kidneys and skeletal muscles had intermediate AUC values. In liver, two metabolites, one of which had the HPLC characteristics of N- demethylmenogarol , were seen. In other organs, the same metabolites were seen later and in small quantities.

Eve A. Olman

Papers

Prospective validation of a pharmacologically based dosing scheme for the cis-diamminedichloroplatinum(II) analogue diamminecyclobutanedicarboxylatoplatinum.

The plasma pharmacokinetics and tissue distribution of dimethyl sulfoxide in mice.

The disposition of the new anthracycline antibiotic, menogarol, in mice

Human Pharmacokinetics and Correlation With Clinical Toxicities of the Anthracycline Antibiotic Menogaril (7-Omen)