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

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 patient's 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 X 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 X predicted change +6,600 (r = 0.97). For the overall combined population, the observed change in platelets = 0.96 X 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 less than 2,000, but 12 patients developed hematocrit less than or equal to 29% and 8 required RBC transfusions. Fifteen patients had nausea and vomiting greater than or equal to grade 2. There were no other nonhematological toxicities observed. In view of continuing documentation of the antitumor activity of carboplatin, these equations allow safe and rational drug dosing of patients with potentially platinum-responsive tumors but with renal function too poor to receive cisplatin. Among the 9 patients in this study evaluable for response, there was 1 partial response in a patient with malignant melanoma and 1 objective response (less than partial response) in a patient with adenocarcinoma of the cervix.

Phase I study of vinblastine and verapamil given by concurrent iv infusion.

Overcoming resistance to chemotherapy is an important goal in cancer treatment. In many systems, resistance to anthracyclines and vinca alkaloids correlates with a diminished intracellular content of drug. In P388 leukemia and Ehrlich ascites tumor, an active outward transport of anthracyclines and vinca alkaloids occurs. Calcium channel blockers, such as verapamil, inhibit this active outward transport and increase intracellular content of vinblastine and anthracyclines in cells resistant to vinca alkaloids and anthracyclines, respectively. We report a phase I trial of vinblastine (1.5 mg/m2 daily as iv continuous infusion X 5 days) in 17 patients and concurrent verapamil in escalating doses. Verapamil was administered as a loading dose (0.02-0.1 mg/kg) followed by a maintenance infusion (0.036-0.18 mg/kg/hour) for 5 1/2 days with continuous cardiac monitoring. There was no apparent augmentation of vinblastine toxicity when vinblastine and verapamil were given concurrently. ECG change was the dose-limiting toxicity. At 0.12 mg/kg/hour, five of nine patients developed first-degree heart block (mean P-R interval, 0.32 seconds; range, 0.23-0.52 seconds). Junctional rhythms were noted in two of 17 patients. Reversible nonspecific T-wave changes were seen in four of 17 patients. Blood pressure and left ventricular ejection fractions (ultrasonic) were not altered. Five of 17 patients had wbc count nadirs less than 2000/mm3, and two of 17 patients had platelet count nadirs less than 100,000/mm3. Four patients experienced neurotoxicity. A mean vinblastine concentration of 2.2 ng/ml (0.55 nM) and a mean verapamil concentration of 290 ng/ml (0.45 microM) were achieved with the concurrent 5-day infusion. The tolerable levels of verapamil obtained appear to be less than those which were reported to inhibit vinblastine efflux in vitro. Additional in vitro experiments at the tolerable doses of vinblastine and verapamil are recommended.

A case report and description of the pharmacokinetic behavior of intrapleurally instilled etoposide.

Etoposide, at a dosage of 100 mg/m2 (156 mg in 250 ml 0.154 M NaCl), was instilled through a thoracostomy tube into the left pleural cavity of a 60-year-old woman with diffuse histiocytic lymphoma and a refractory, recurrent, malignant left pleural effusion. Etoposide concentrations in plasma and pleural cavity fluid were measured by a reverse-phase HPLC system with a C18-reverse phase column, a mobile phase of methanol: H2O (55:45) pumped at 1.2 ml/min, and detection by absorbance at 254 nm. Pleurodesis was successfully accomplished by this maneuver and there were no adverse clinical consequences. Absorption of etoposide from the pleural cavity was slow (approximately 0.2 ml/min). The pleural cavity exposure to etoposide, as measured by the area under the curve, was 46 times greater than if a similar dose had been given IV. Conversely, systemic exposure to etoposide, as assessed by plasma AUC, was less than 50% that associated with IV injection of a similar dose.

Pharmacokinetics and dosage reduction of cis-diammine(1,1-cyclobutanedicarboxylato)platinum in patients with impaired renal function.

cis-Diammine(1,1-cyclobutanedicarboxylato)platinum (CBDCA) is a nonnephrotoxic but myelosuppressive analogue of cisplatin (DDP) with greatly reduced protein binding and greatly increased renal excretion. Thus, CBDCA might produce undue toxicity in patients with decreased renal function. Twenty-two patients [14 females and 8 males; median age, 66 (range, 35 to 83); median Karnofsky performance status, 70 (range, 40 to 90)] with refractory tumors and renal dysfunction [creatinine clearance (CCr) 6 to 83 ml/min] were treated with 31 courses of i.v. bolus CBDCA every 4 to 5 weeks. Dosages were determined by pretreatment CCr. Patients with CCr greater than or equal to 40 ml/min received 400 mg/sq m; patients with CCr 20 to 39 ml/min received 250 mg/sq m; and patients with CCr 0 to 19 ml/min received 150 mg/sq m. Toxicities were assessed by weekly clinical and laboratory assessment. Responses were assessed in patients with measurable disease. Plasma pharmacokinetics and urinary excretion of total and ultrafilterable platinum were measured with flameless atomic absorption spectrometry. Observed toxicities were similar to those in patients with normal renal function. Myelosuppression, especially thrombocytopenia, was the major toxicity. Nausea and vomiting were mild to moderate. There was no ototoxicity, neurotoxicity, or nephrotoxicity or reduction in CCr due to CBDCA. Total body clearance of ultrafilterable platinum correlated highly with CCr. The percentage of reduction in platelet count correlated highly and linearly with the area under the curve (AUC) of plasma-ultrafilterable platinum. However, for any AUC, there was 17% greater platelet reduction in patients who had previously received extensive myelosuppressive chemotherapy than in nonpretreated patients. Since total body clearance is proportional to CCr, platelet reduction is proportional to AUC, and total body clearance = dosage/AUC, we have derived an equation to calculate a dosage that will produce a desired reduction in platelet count. Calculations for theoretical patients (both pretreated and nonpretreated) with CCr of 100 ml/min produce dosages very close to maximum tolerated dosages derived in actual Phase I trials. The actual clinical utility of these predictive equations must await validation in prospective studies with larger numbers of patients.

Phase I clinical and pharmacologic trial of carboplatin daily for 5 days.

Twenty-two patients with refractory tumors received 64 courses of iv bolus carboplatin every day X 5, every 4-5 weeks. All patients are evaluable for toxicity and 18 are evaluable for response. For solid tumor phase II studies, a dose of 77 mg/m2/day X 5 is recommended for patients who have received prior chemotherapy. Patients with no prior chemotherapy experience should receive 99 mg/m2/day X 5. The major dose-limiting side effect is dose-related thrombocytopenia. Courses of carboplatin on this schedule should be repeated every 5 weeks to avoid cumulative wbc count toxicity, since leukopenia frequently did not occur until Day 28. Other toxic effects observed were nausea and vomiting and lower-extremity myalgias and arthralgias. There was no evidence of hearing loss, mucosal damage, or changes in liver or renal function tests of any patient while in this study. Therapeutic responses were seen in four patients: one partial response in renal cancer of 9+ months' duration; one partial response in head and neck cancer of 7+ months' duration; and objective responses in melanoma and colorectal carcinoma of 6 months' duration.

The disposition of the new anthracycline antibiotic, menogarol, 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.

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

We defined the plasma and tissue concentrations and pharmacokinetics of dimethyl sulfoxide (DMSO) in 22-34 g male Swiss Webster mice injected i.v. with 15% DMSO at a dosage of 1.5 mg per g. Concentrations of DMSO in alkalinized, perchloric acid extracts of tissue and plasma were determined by gas-liquid chromatography. Plasma concentrations of DMSO declined in a biexponential fashion that was well described by the equation Ct = 2.36 exp(-0.449 t) + 1.28 exp(-0.00768 t), indicating a t 1/2 (alpha) of 1.5 min and t 1/2 (beta) of 90 min. DMSO was rapidly and extensively distributed through tissues and was not concentrated in any particular tissue, although at 1 min after injection, the brain contained the lowest concentration of DMSO of any tissue studied. By 8 hr after injection, there was little DMSO in plasma or any tissue. Intravenous injection of DMSO produced neuro-muscular disturbances, hemolysis, and hemoglobinuria in all animals. Intravenous injection of DMSO produced little increase in plasma osmolality and did not produce any histological evidence of central nervous system or renal tubular damage.