W. J. Loos

Phase I and pharmacologic study of oral topotecan administered twice daily for 21 days to adult patients with solid tumors.

PURPOSEnTopotecan is a specific inhibitor of topoisomerase I. Recently bioavailability of an oral formulation of approximately 30% with limited variability was reported. We conducted a phase I and pharmacokinetic study of the oral formulation of topotecan to characterize the maximum-tolerated dose (MTD), toxicities, pharmacokinetics, and antitumor effects in patients with refractory malignancies.nnnPATIENTS AND METHODSnPatients were treated with oral topotecan given twice daily for 21 days, with cycles repeated every 28 days. In subsequent cohorts, the dose was escalated from 0.15 to 0.6 mg/m2 twice daily. Pharmacokinetics were performed on day 1 and 8 of the first course using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic methods.nnnRESULTSnThirty-one patients entered the study; one patient was not assessable for toxicity and response as therapy was prematurely interrupted on request of the patient who had not experienced toxicity. Thirty patients received a total of 59 courses. The dose-limiting toxicity (DLT) was reached at a dose of 0.6 mg/m2 twice daily and consisted of diarrhea, which started subacutely at a median onset on day 15 (range, 12 to 20) and resolved after a median of 8 days (range, 7 to 16). Other toxicities were mild, including leukocytopenia, thrombocytopenia, nausea, and vomiting. The MTD was 0.5 mg/m2 twice daily. No responses were observed. Pharmacokinetics showed a substantial variation of the area under the plasma concentration-time curve at time point t [AUC(t)] of topotecan and ring-opened product hydroxyacid. A significant correlation was observed between the percentage of decrease in WBC count versus the AUC(t) of topotecan (r = .75), which was modeled by a sigmoidal maximal effect concentration (Emax) function.nnnCONCLUSIONnThe DLT in this phase I study for chronic oral topotecan for 21 days was diarrhea. The recommended dose for phase II studies is 0.5 mg/m2 twice daily.

Five days of oral topotecan (hycamtin®), a phase I and pharmacological study in adult patients with solid tumours

Topotecan is a specific inhibitor to topoisomerase I. An oral formulation of topotecan is available with a bioavailability of 32-44% in humans. A phase I and pharmacological study of the oral formulation of topotecan administered daily for 5 days every 21 days was performed in adult patients with solid tumours to determine the maximum tolerated dose (MTD). Adult patients with a WHO performance status < or = 2 adequate haematological, hepatic and renal functions, with malignant solid tumours refractory to standard forms were entered into the study. Pharmacokinetics were performed on days 1 and 4 of the first course using a validated high performance liquid chromatographic assay. 29 patients entered the study, all patients were evaluable for toxicity and response. The doses studied in the 29 patients were 1.2, 1.8, 2.3, 2.7 mg/m2/day and a fixed dose of 4 mg/day without surface area adjustment. A total of 109 courses were given. Dose limiting toxicity (DLT) was reached at a dose of 2.7 mg/m2/day and consisted of CTC (NCI-Common Toxicity Criteria) grade IV granulocytopenia. The regimen was well tolerated. Non-haematological toxicities were mild, including fatigue, anorexia, nausea, vomiting and diarrhoea. A significant correlation was observed between the percentage decrease in white blood cells versus the area under the curve (AUC(t)) of topotecan lactone (R = 0.76 P < 0.01) which was modelled by a sigmoidal Emax function. The correlation coefficient between the absolute topotecan dose administered and the AUC(t) was R = 0.52 (P = 0.04). Pharmacokinetics of the fixed dose of 4 mg/day were comparable to the 2.3 mg/m2/day dose. DLT in this phase I study of five daily doses of oral topotecan every 21 days was granulocytopenia. The recommended dose for phase II studies is 2.3 mg/m2/day or alternatively, a fixed dose of 4 mg/day.

Early cessation of the clinical development of LiPlaCis, a liposomal cisplatin formulation

PURPOSEnTo evaluate the safety and tolerability of LiPlaCis, a liposomal formulated platinum compound, in patients with solid tumours and to determine the maximum tolerated dose (MTD) of intravenous (i.v.) LiPlaCis. and to assess plasma and urine pharmacokinetics and plasma biomarkers.nnnPATIENTS AND METHODSnPatients with solid tumours without standard therapeutic options were enrolled to receive LiPlaCis administered as a 1 h infusion without additional hydration every 3weeks until RECIST progression or unacceptable toxicity. Cohorts of 3-6 patients were treated at each dose level until MTD was reached.nnnRESULTSnEighteen patients were enrolled and 64 cycles were delivered. At the first dose level 3 patients experienced an infusion reaction. Despite prophylactic pre-medication and prolongation of the infusion to 2 h in further patients, three other patients had mild acute infusion reactions. Toxicity at the fifth dose level of 120 mg consisted of grade 2 renal toxicity reversible after hydration in 2 patients and grade 4 thrombocytopaenia in one of these patients. Peak plasma concentrations and AUC were dose proportional. The interpatient variability in the clearance of total LiPlaCis-derived platinum was 41%. Platinum was excreted via the urine mainly during the first 24 h after administration. Investigated plasma biomarkers sPLA(2) and SC5b-9 were related to, but not predictive for, acute infusion reactions.nnnCONCLUSIONnThe observed safety profile suggests no benefit over standard cisplatin formulations and LiPlaCis will require reformulation to enable further development.

Environmental and Genetic Factors Affecting Transport of Imatinib by OATP1A2

The bioavailability of orally administered imatinib is >90%, although the drug is monocationic under the acidic conditions in the duodenum. In vitro, we found that imatinib is transported by the intestinal uptake carrier organic anion transporting polypeptide (OATP1A2) and that this process is sensitive to pH, rosuvastatin, and genetic variants. However, in a study in patients with cancer, imatinib absorption was not associated with OATP1A2 variants and was unaffected by rosuvastatin. These findings highlight the importance of verifying in a clinical setting the drug–transporter interactions observed in in vitro tests.

Mechanism-based models for topotecan-induced neutropenia

A semiphysiologic pharmacokinetic‐pharmacodynamic model was applied to describe topotecan‐induced neutropenia, to quantify interindividual and intraindividual pharmacodynamic variability, and to study the effect of covariates on the model.

Factors affecting pharmacokinetic variability of oral topotecan: A population analysis

The aim of this study was to characterise the pharmacokinetics of the anticancer agent topotecan, and explore the influence of patient covariates and interoccasion variability on drug disposition. Data were obtained from 190 patients who received the drug as a 30-min infusion (N=72) or orally (N=118). The population model was built with the use of NONMEM to identify candidate covariates, and obtain models for clearance (CL) and volume of distribution. The final models were based on first-order absorption with lag-time (oral data), and a two-compartment model with linear elimination from the central compartment. The Cockcroft–Gault creatinine clearance (CrCl) and WHO performance status (PS) were the only significant covariates: CL=(12.8+2.1 × CrCl) × (1−0.12 × PS). For the volume of distribution, a correlation was found between body weight and the central volume (V1)=0.58 × body weight. Based on the structural models, a limited-sampling strategy was developed with minor bias and good precision that can be applied a posteriori using timed samples obtained at 1.5, and 6u2009h after the administration of topotecan. In conclusion, a population pharmacokinetic model for topotecan has been developed that incorporates measures of renal function and PS to predict CL. In combination with drug monitoring, the limited sampling strategy allows individualised treatment for patients receiving oral topotecan.

Differential modulation of cisplatin accumulation in leukocytes and tumor cell lines by the paclitaxel vehicle Cremophor EL

BACKGROUNDnSeveral clinical studies have shown that polychemotherapy with the taxanes paclitaxel or docetaxel preceded or followed by cisplatin is associated with important schedule-dependent differences in toxicities, such as leukocytopenia. In general, the pharmacokinetics of both drugs during the combined treatment are unaltered, suggesting that a pharmacodynamic interaction might have occurred.nnnMATERIALS AND METHODSnIn order to gain insight into this pharmacologic interaction, we performed in vitro drug accumulation studies using peripheral blood leukocytes and a panel of tumor and non-malignant cell lines with paclitaxel and docetaxel, as well as with their respective formulation vehicles Cremophor EL and Tween 80.nnnRESULTSnOur results show a significant reduction in the intracellular cisplatin concentration in leukocytes of up to 42% in the presence of Cremophor EL and Tween 80 as compared to the control. This pharmacodynamic interaction of these surfactants with cisplatin seems to be specific for haematopoietic cells, and does not occur in solid tumor cells.nnnCONCLUSIONnThe present data suggest that the pharmaceutical vehicles Cremophor EL and Tween 80 might contribute to the reduced cisplatin-associated myelotoxicity observed in the clinical combination chemotherapy studies with paclitaxel and docetaxel.

Irinotecan pharmacokinetics-pharmacodynamics: the clinical relevance of prolonged exposure to SN-38

We have shown previously that the terminal disposition half-life of SN-38, the active metabolite of irinotecan, is much longer than earlier thought. Currently, it is not known whether this prolonged exposure has any relevance toward SN-38-induced toxicity. Here, we found that SN-38 concentrations present in human plasma for up to 3 weeks after a single irinotecan infusion induce significant cytotoxicity in vitro. Using pharmacokinetic data from 26 patients, with sampling up to 500u2009h, relationships were evaluated between systemic exposure (AUC) to SN-38 and the per cent decrease in absolute neutrophil count (ANC) at nadir, or by taking the entire time course of ANC into account (AOC). The time course of SN-38 concentrations (AUC500u2009h) was significantly related to this AOC (P<0.001). Based on these findings, a new limited-sampling model was developed for SN-38 AUC500u2009h using only two timed samples: AUC500u2009h=(6.588×C2.5u2009h)+(146.4×C49.5u2009h)+15.53, where C2.5u2009h and C49.5u2009h are plasma concentrations at 2.5 and 49.5u2009h after start of infusion, respectively. The use of this limited-sampling model may open up historic databases to retrospectively obtain information about SN-38-induced toxicity in patients treated with irinotecan.

Associations Between ABCC2 Polymorphisms and Cisplatin Disposition and Efficacy

ABCC2 (MRP2, cMOAT) expression has been implicated in cisplatin resistance in vitro. In mice, cisplatin disposition and toxicity were unaffected by Abcc2 knockout (Abcc2−/−). Moreover, in cancer patients (n = 237), cisplatin pharmacokinetics (P > 0.12) and efficacy (P > 0.41) were not associated with seven of the single‐nucleotide polymorphisms (SNPs) in ABCC2. These SNPs were also not correlated with ABCC2 expression in the NCI60 panel (P > 0.26) or with cisplatin‐induced cytotoxicity (P = 0.21). These findings highlight the importance of verifying drug–transporter interactions with in vitro tests in humans.

Dose and schedule-finding study of oral topotecan and weekly cisplatin in patients with recurrent ovarian cancer

Both weekly cisplatin chemotherapy and single agent topotecan have proven to be effective in recurrent ovarian cancer. Preclinical data show synergism between cisplatin and topotecan. Side effects for this combination are drug sequence dependent and predominantly haematologic. Since preclinical data suggest that Cremophor EL (CrEL), the formulation vehicle of paclitaxel, has a protective effect on haematological toxicity of cisplatin, CrEL was added to the combination cisplatin and topotecan. In this phase I study, escalating doses of oral topotecan administered on day 1, 2, 8, 9, 15, 16, 29, 30, 36, 37, 43, 44 were combined with weekly cisplatin 70 mg m–2d–1on day 1, 8, 15, 29, 36, 43 (scheme A) or with the presumably less myelotoxic sequence weekly cisplatin day 2, 9, 16, 30, 37, 44 (scheme B). In scheme C, CrEL 12 ml was administered prior to cisplatin in the sequence of Scheme A. 18 patients have received a total of 85 courses. In scheme A 4/10 patients, all treated with topotecan 0.45 mg m–2d–1, experienced DLT: 1 patient had vomiting grade 4, 1 patient had grade 4 neutropenia >5 days, 1 patient had >2 weeks delay due to thrombocytopenia and 1 patient due to neutropenia. Both patients in scheme B (topotecan 0.45 mg m–2d–1) had DLT due to a delay > 2 weeks because of prolonged haematological toxicity. No DLT was observed in the first 3 patients in scheme C (topotecan 0.45 mg m–2d–1). However, 2 out of 3 patients treated at dose level topotecan 0.60 mg m–2d–1in scheme C experienced DLT due to >2 weeks delay because of persistent thrombocytopenia or neutropenia. We conclude that there is a modest clinical effect of CrEL on haematological toxicity for this cisplatin-based combination regimen, which seems to reduce these side effects but does not really enable an increase of the oral topotecan dose.