Population pharmacokinetic/pharmacodynamic analyses of pemetrexed and neutropenia: effect of vitamin supplementation and differences between Japanese and Western patients.

PURPOSE: The objectives of the analysis were to characterize the time course of neutropenia after pemetrexed administration using an established semimechanistic-physiologic model, characterize the relationship between pemetrexed exposure and neutropenia, and describe differences in neutropenic response by vitamin supplementation status and between Japanese and Western patients. EXPERIMENTAL DESIGN: An eight-compartment population pharmacokinetic/pharmacodynamic model was used to describe the absolute neutrophil count (ANC)-time profile (neutropenic response) following pemetrexed doses of 300 to 1,400 mg/m(2) administered every 21 days. The analyses pooled data from 13 studies including 279 patients (161 supplemented with oral folic acid and intramuscular vitamin B(12), and 118 unsupplemented; 248 Western and 31 Japanese) who received 857 treatment cycles. RESULTS: Vitamin supplementation status, ethnic origin, and drug exposure were the dominant predictors of neutropenic response. Vitamin supplementation diminishes neutropenic response to pemetrexed. Model-predicted ANC nadirs for the "typical" Western patient receiving 500 mg/m(2) pemetrexed +/- vitamin supplementation were 2.74 x 10(9)/L and 1.70 x 10(9)/L, respectively. Japanese patients had a less pronounced neutropenic response to pemetrexed relative to Western patients. The model-predicted ANC nadir for Japanese patients receiving 500 mg/m(2) pemetrexed with vitamin supplementation was 2.66 x 10(9)/L. Values for the 1,000 mg/m(2) dose with vitamin supplementation were 1.91 x 10(9)/L and 1.34 x 10(9)/L for Japanese and Western patients, respectively. Increased albumin, decreased cystathionine, and decreased body surface area were also associated with increased neutropenic response. CONCLUSIONS: The neutropenic response to higher pemetrexed doses administered with vitamin supplementation is tolerable. All other factors equal, Japanese patients have a lesser neutropenic response to pemetrexed relative to Western patients.

Phase I and pharmacokinetic study of pemetrexed plus cisplatin in chemonaive patients with locally advanced or metastatic malignant pleural mesothelioma or non-small cell lung cancer.

PURPOSE: Pemetrexed is approved as monotherapy and in combination with cisplatin. The established combination dose was identified before the addition of folic acid and vitamin B(12) to the treatment regimen. We evaluated the toxicity and pharmacokinetics (PK) of higher pemetrexed doses with cisplatin and vitamin supplementation. EXPERIMENTAL DESIGN: Patients with malignant pleural mesothelioma or non-small cell lung cancer received pemetrexed doses from 500 to 900 mg/m(2) + 75 mg/m(2) cisplatin once every 21 days. Folic acid and vitamin B(12) were administered per label recommendations. RESULTS: Twenty-one patients received a combined total of 84 cycles. The maximum tolerated dose was 900 mg/m(2) pemetrexed + 75 mg/m(2) cisplatin. Dose-limiting toxicities at this dose included grade 3 anemia, bronchopneumonia, and neutropenia, and 1 death from sepsis secondary to grade 4 febrile neutropenia, considered possibly related to study drugs. The recommended dose was 800 mg/m(2) pemetrexed + 75 mg/m(2) cisplatin. Pemetrexed PK were consistent across doses; pemetrexed did not seem to affect total or free platinum PK. CONCLUSIONS: Pemetrexed with vitamin supplementation was safe and well tolerated at higher doses than the currently established 500 mg/m(2) + 75 mg/m(2) cisplatin. Based on this study, the recommended dose would be 800 mg/m(2) pemetrexed + 75 mg/m(2) cisplatin. However, recent studies showed a lack of improved efficacy for 900 or 1,000 mg/m(2) single-agent pemetrexed versus 500 mg/m(2) and a lack of PK/pharmacodynamic exposure-response relationship for the pemetrexed/cisplatin combination across pemetrexed exposures corresponding to this dose range. Based on currently available evidence, we recommend retaining the established dose.

Pharmacokinetic evaluation of platinum derived from cisplatin administered alone and with pemetrexed in head and neck cancer patients.

PURPOSE: This phase I study characterized the pharmacokinetics of free and total platinum derived from cisplatin administered alone and in combination with pemetrexed. Secondary objectives were to assess the pharmacokinetics of pemetrexed when it is combined with cisplatin as well as to evaluate the safety profile and document antitumor activity associated with this combination. METHODS: An open-label, two-arm, cross-over phase 1 study was performed in patients with squamous cell carcinoma of the head and neck, age > or =18 years, an Eastern Cooperative Oncology Group performance status of 0-2, and adequate organ function. Blood samples were taken and pharmacokinetics evaluated for the first two cycles using noncompartmental analysis. Patients received either pemetrexed (500 mg m(-2)) plus cisplatin (75 mg m(-2)) administered in cycle 1 followed by cisplatin alone in cycle 2; or in the reverse order (i.e., cisplatin alone in cycle 1 followed by pemetrexed plus cisplatin in cycle 2). Each treatment cycle was 21 days and patients received folic acid, vitamin B(12) supplementation, and dexamethasone prophylaxis. After the first two cycles, patients continued study treatment with pemetrexed plus cisplatin every 3 weeks up to a maximum of six total treatment cycles. Toxicities were graded by the investigators according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 3.0. RESULTS: A total of 13 patients were treated; one patient was discontinued from the study after cycle 1 for failure to meet baseline eligibility criteria for renal function. The ratios and 90% confidence intervals (CI) comparing the pharmacokinetics for cisplatin administered with pemetrexed to those for cisplatin administered alone for free platinum were: C(max) = 1.08 (CI: 0.92, 1.27) and AUC = 0.93 (CI: 0.82, 1.06); and, total platinum were: C(max) = 0.97 (CI: 0.88, 1.06) and AUC = 0.87 (CI: 0.81, 0.93). These results indicate that platinum pharmacokinetics (free and total) are similar, whether cisplatin is administered alone or combined with pemetrexed. The pemetrexed pharmacokinetic results were consistent with those from previous single-agent pemetrexed studies and a previous study of pemetrexed in combination with cisplatin. The combination of pemetrexed and cisplatin did not show any unexpected toxicities. Consistent with the platinum pharmacokinetic results, co-administration with pemetrexed did not appear to enhance cisplatin-related toxicities. Of the 13 treated patients, 11 had stable disease as the best overall response and 2 had progressive disease. CONCLUSIONS: The pharmacokinetics of free platinum derived from cisplatin were not altered by co-administration with pemetrexed, and in agreement with this, no unexpected cisplatin-induced toxicities were observed when these drugs were combined.

Phase I and pharmacokinetic study of pemetrexed with high-dose folic acid supplementation or multivitamin supplementation in patients with locally advanced or metastatic cancer.

PURPOSE: This phase I study evaluated the effect of folate supplementation on the toxicity, tolerability, and pharmacokinetics of pemetrexed in patients with locally advanced or metastatic cancer. It also examined two different types of vitamin supplementation and whether the extent of prior myelosuppressive therapy affected pemetrexed tolerability. PATIENTS AND METHODS: Patients received a 10-min infusion of 600 to 14,00 mg/m(2) pemetrexed every 3 weeks. Patients were stratified into cohorts by pretreatment status [lightly pretreated (LPT) or heavily pretreated (HPT)] and were supplemented with intermittent high-dose folic acid (HDFA) or with continuous daily multivitamins (MVI) containing nutritional doses of folic acid. Pemetrexed plasma pharmacokinetics were evaluated for cycle 1. RESULTS: Sixty-two HDFA patients (28 HPT and 34 LPT) were treated with 204 cycles of pemetrexed, and 43 MVI patients (20 HPT and 23 LPT) were treated with 182 cycles. Hematologic dose-limiting toxicities included grade 4 neutropenia (5 of 105 patients), grade 4 thrombocytopenia (4 of 105 patients), and febrile neutropenia (3 of 105 patients). Nonhematologic toxicities included fatigue, vomiting, diarrhea, and nausea. Pemetrexed doses of 800 and 1,050 mg/m(2) were well tolerated when administered with vitamin supplementation to HPT and LPT patients, respectively. There were no clinically relevant differences in toxicities or pemetrexed pharmacokinetics for LPT versus HPT patients or for patients receiving HDFA versus daily MVI supplementation. CONCLUSIONS: The pemetrexed doses tolerated in this study with vitamin supplementation were significantly higher than those tolerated in earlier studies without supplementation, and toxicities were independent of the type of vitamin supplementation or prior myelosuppressive treatment. The recommended dose of pemetrexed is 1,050 mg/m(2) in LPT patients and 800 mg/m(2) in HPT patients, irrespective of the type of vitamin supplementation.

A phase I and pharmacokinetic study of pemetrexed plus irinotecan in patients with advanced solid malignancies.

PURPOSE: The main objectives of this phase I and pharmacokinetic, open-label study were to characterize the principal toxicities and determine the maximum tolerated dose of the multitargeted antifolate pemetrexed administered in combination with irinotecan. The study also sought to detect major pharmacokinetic drug-drug interactions between these agents and preliminary evidence of antitumor activity in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: Pemetrexed was administered as a 10-min i.v. infusion followed by irinotecan given i.v. over 90 min every 3 weeks to patients with advanced solid malignancies. The study objectives were first pursued in heavily pretreated patients and then in lightly pretreated patients who also received vitamin supplementation. RESULTS: Twenty-three heavily pretreated patients enrolled in the first stage of the study, and the maximum tolerated dose level of pemetrexed/irinotecan without vitamin supplementation was 400/250 mg/m(2); further dose escalation was precluded by severe neutropenia that was protracted and/or associated with fever. In the second stage of the study, 28 lightly pretreated patients were administered pemetrexed/irinotecan with vitamin supplementation; these patients tolerated pemetrexed/irinotecan at a dose level of 500/350 mg/m(2), which reflected clinically relevant single-agent doses of both agents. No major pharmacokinetic interactions between the agents were evident. Four patients, two patients each with colorectal cancer refractory to fluoropyrimidines and advanced mesothelioma, had partial responses. CONCLUSIONS: The pemetrexed/irinotecan regimen is well tolerated in patients with advanced solid malignancies at clinically relevant single-agent doses. The recommended dose level of pemetrexed/irinotecan for subsequent disease-directed evaluations involving lightly pretreated patients is 500/350 mg/m(2) every 3 weeks with vitamin supplementation.

A phase I study of pemetrexed (ALIMTA) and cyclophosphamide in patients with locally advanced or metastatic breast cancer.

PURPOSE: Determine the maximum tolerated dose (MTD) of pemetrexed and cyclophosphamide combination therapy for patients with locally advanced or metastatic breast cancer. EXPERIMENTAL DESIGN: Patients with locally advanced or metastatic breast cancer and WHO performance status 0 to 2 were eligible. Pemetrexed (range, 400-2,400 mg/m(2)) was administered on day 1 of a 21-day schedule followed by cyclophosphamide (range, 400-800 mg/m(2)). Folic acid and vitamin B(12) supplementation began 1 to 2 weeks before the first pemetrexed dose. RESULTS: Fifty-seven pretreated patients were enrolled and received 342 cycles (median, 4 cycles; range, 1-26) through 14 dose levels. The MTD of pemetrexed was 2,400 mg/m(2) (combined with cyclophosphamide, 600 mg/m(2)) with dose-limiting toxicities of grade 4 neutropenia with grade 4 infection and grade 3 diarrhea. Other grade 3 or 4 toxicities included (febrile) neutropenia, thrombocytopenia, anemia, elevated alanine aminotransferase/aspartate aminotransferase, and diarrhea. Pharmacokinetic analysis indicated that pemetrexed clearance and central volume of distribution were 40% lower than single-agent reference data, yielding a 68% increase in total systemic exposure and a 56% increase in maximal plasma concentration. Among the 50 patients evaluable for efficacy, 13 (26%) patients had a partial response and 17 (34%) patients had stable disease. CONCLUSIONS: Pemetrexed was generally well tolerated. The observed toxicities were consistent with the known toxicity profiles of pemetrexed and cyclophosphamide. Considering the MTD and the toxicity and efficacy results in this and prior studies, a low (600 mg/m(2)) and a high (1,800 mg/m(2)) dose of pemetrexed with cyclophosphamide (600 mg/m(2)) will be evaluated in the consecutive prospective randomized phase II study.

Phase I and pharmacokinetic study of pemetrexed administered every 3 weeks to advanced cancer patients with normal and impaired renal function.

PURPOSE: This phase I study was conducted to determine the toxicities, pharmacokinetics, and recommended doses of pemetrexed in cancer patients with normal and impaired renal function. PATIENTS AND METHODS: Patients received a 10-minute infusion of 150 to 600 mg/m2 of pemetrexed every 3 weeks. Patients were stratified for independent dose escalation by measured glomerular filtration rate (GFR) into four cohorts ranging from > or = 80 to less than 20 mL/min. Pemetrexed plasma and urine pharmacokinetics were evaluated for the first cycle. Patients enrolled after December 1999 were supplemented with oral folic acid and intramuscular vitamin B12. RESULTS: Forty-seven patients were treated with 167 cycles of pemetrexed. Hematologic dose-limiting toxicities occurred in vitamin-supplemented patients (two; 15%) and non-supplemented patients (six; 18%), and included febrile neutropenia (four patients) and grade 4 thrombocytopenia (two patients). Nonhematologic toxicities included fatigue, diarrhea, and nausea, and did not correlate with renal function. Accrual was discontinued in patients with GFR less than 30 mL/min after one patient with a GFR of 19 mL/min died as a result of treatment-related toxicities. Pemetrexed plasma clearance positively correlated with GFR (r2 = 0.736), resulting in increased drug exposures in patients with impaired renal function. With vitamin supplementation, pemetrexed 600 mg/m2 was tolerated by patients with a GFR > or = 80 mL/min, whereas patients with a GFR of 40 to 79 mL/min tolerated a dose of 500 mg/m2. CONCLUSION: Pemetrexed was well tolerated at doses of 500 mg/m2 with vitamin supplementation in patients with GFR > or = 40 mL/min. Additional studies are needed to define appropriate dosing for renally impaired patients receiving higher dose pemetrexed with vitamin supplementation.

Two drug interaction studies evaluating the pharmacokinetics and toxicity of pemetrexed when coadministered with aspirin or Ibuprofen in patients with advanced cancer.

PURPOSE: Pemetrexed is an antimetabolite that is structurally similar to methotrexate. Because nonsteroidal anti-inflammatory drugs (NSAID) impair methotrexate clearance and increase its toxicity, we evaluated the pharmacokinetics and toxicity of pemetrexed when coadministered with aspirin or ibuprofen in advanced cancer patients. EXPERIMENTAL DESIGN: In two independent, randomized, crossover drug interaction studies, cancer patients with a creatinine clearance (CrCl) > or =60 mL/min received an NSAID (aspirin or ibuprofen) with either the first or the second dose of pemetrexed (cycle 1 or 2). Pemetrexed (500 mg/m(2)) was infused i.v. on day 1 of a 21-day cycle, and all patients were supplemented with oral folic acid and i.m. vitamin B(12). Aspirin (325 mg) or ibuprofen (400 mg; 2 x 200 mg) was given orally every 6 hours, starting 2 days before pemetrexed administration, with the ninth and final dose taken 1 hour before infusion. Pemetrexed pharmacokinetics with and without concomitant NSAID treatment were compared for cycles 1 and 2. RESULTS: Data from 27 patients in each study were evaluable for the analysis of pemetrexed pharmacokinetics. Coadministration of aspirin did not alter pemetrexed pharmacokinetics; however, ibuprofen coadministration was associated with a 16% reduction in clearance, a 15% increase in maximum plasma concentration, and a 20% increase in area under the plasma concentration versus time curve but no significant change in V(ss) compared with pemetrexed alone. No febrile neutropenia occurred in any patient, and no increase in pemetrexed-related toxicity was associated with NSAID administration. CONCLUSIONS: Pemetrexed (500 mg/m(2)) with vitamin supplementation is well tolerated and requires no dosage adjustment when coadministered with aspirin (in patients with CrCl > or =60 mL/min) or ibuprofen (in patients with CrCl > or =80 mL/min).

A semimechanistic-physiologic population pharmacokinetic/pharmacodynamic model for neutropenia following pemetrexed therapy.

PURPOSE: The objectives of these analyses were to (1) develop a semimechanistic-physiologic population pharmacokinetic/pharmacodynamic (PK/PD) model to describe neutropenic response to pemetrexed and to (2) identify influential covariates with respect to pharmacodynamic response. PATIENTS AND METHODS: Data from 279 patients who received 1,136 treatment cycles without folic acid or vitamin B12 supplementation during participation in one of eight phase II cancer trials were available for analysis. Starting doses were 500 or 600 mg pemetrexed per m2 body surface area (BSA), administered as 10-min intravenous infusions every 21 days (1 cycle). The primary analyses included 105 patients (279 cycles) for which selected covariates-including vitamin deficiency marker data (i.e., homocysteine, cystathionine, methylmalonic acid, and methylcitrate [I, II, and total] plasma concentrations)-were available. Classical statistical multivariate regression analyses and a semimechanistic-physiologic population PK/PD model were used to evaluate neutropenic response to single-agent pemetrexed administration. RESULTS: The timecourse of neutropenia following single-agent pemetrexed administration was adequately described by a semimechanistic-physiologic model. Population estimates for system-based model parameters (i.e., baseline neutrophil count, mean transit time, and the feedback parameter), which mathematically represent current understanding of the process and physiology of hematopoiesis, were consistent with previously reported values. The population PK/PD model included homocysteine, cystathionine, albumin, total protein, and BSA as covariates relative to neutropenic response. CONCLUSION: These results support the programmatic decision to introduce folic acid and vitamin B12 supplementation during pemetrexed clinical development as a means of normalizing patient homocysteine levels, thereby managing the risk of severe neutropenia secondary to pemetrexed administration. The current results also suggest that the addition of vitamin B6 supplementation to normalize patient cystathionine levels may further decrease the incidence of grade 4 neutropenia following pemetrexed administration. The results also suggest the use of folic acid as a means of lessening hematologic toxicity following administration of cytotoxic agents other than antifolates.

Population pharmacokinetic analysis of ten phase II clinical trials of pemetrexed in cancer patients.

PURPOSE: The objectives of these population pharmacokinetic analyses were to (1) assess the overall disposition of pemetrexed, (2) characterize between-patient and within-patient variability and identify influential covariates with respect to pemetrexed pharmacokinetics; and, (3) provide individual empirical Bayesian estimates of pharmacokinetic parameters for use in a subsequent pharmacokinetic/pharmacodynamic evaluation of neutropenia following pemetrexed administration. PATIENTS AND METHODS: Data from 287 patients who received 441 cycles without folic acid or vitamin B12 supplementation during participation in one of ten phase II cancer trials were evaluated by population pharmacokinetic analysis using NONMEM. Starting doses were 500 or 600 mg pemetrexed per m2 body surface area, administered as 10-min intravenous infusions every 21 days (1 cycle). The model was developed using data from eight of the ten studies. Predictive performance was evaluated using data from the other two studies. RESULTS: The population pharmacokinetics of pemetrexed administered as a 10-min intravenous infusion are well characterized by a two-compartment model. Typical values of total systemic clearance, central volume of distribution, distributional clearance, and peripheral volume of distribution were 91.6 ml/min, 12.9 l, 14.4 ml/min, and 3.38 l, respectively. Based on these parameter estimates, the terminal elimination half-life of pemetrexed was approximately 3.5 h. Renal function was identified as a covariate with respect to total systemic clearance, and body surface area as a covariate with respect to the central volume of distribution. CONCLUSION: Total systemic exposure (AUC) for a given dose of pemetrexed increases as renal function decreases. Since pharmacodynamic analyses have shown that AUC and not C (max) is the primary determinant of neutropenic response to pemetrexed, this suggests that dose adjustments based on renal function, rather than body surface area, might be considered for pemetrexed.

Clinical application of a semimechanistic-physiologic population PK/PD model for neutropenia following pemetrexed therapy.

PURPOSE: The objective of these analyses was to examine the effect of variations in the explanatory factors of neutropenic response, identified by semimechanistic-physiologic population pharmacokinetic/pharmacodynamic (PK/PD) modeling, on clinically important features of the absolute neutrophil count (ANC)-time profile (e.g, the nadir of the ANC [NANC], its timing [T (Nadir)], and the timecourse of recovery [T (Rec)]). METHODS: Correlation analyses were used to evaluate the relationship of NANC, T (Nadir), and T (Rec) as a function of overall systemic exposure (AUC) and each of the covariates contained in the population PK/PD model. Simulations using the final PK/PD model were used to generate complete ANC-time profiles. Frequency counts of NANCs from the simulated profiles were used to quantitatively explore differences in the incidence and severity of neutropenia associated with a variety of scenarios (500 mg/m2 versus 600 mg/m2, normal vitamin deficiency markers versus elevated vitamin deficiency markers, and body surface area-based versus renal function-based dosing) and to evaluate the effect of individual explanatory factors with respect to neutropenic response. RESULTS: Information obtained from correlation analysis and simulations was helpful in quantitatively exploring the impact of dose, exposure, and/or patient characteristics on neutropenic response. The information gained from these simulations provided supportive evidence for the decision to routinely include vitamin supplementation during pemetrexed treatment as a means of managing the risk of severe neutropenia secondary to pemetrexed administration. These techniques also provided information regarding the specific T (Nadir) and T( Rec) for inclusion in product labeling and suggested that a 14-day treatment cycle might be feasible for pemetrexed. CONCLUSION: For population PK/PD models, to provide useful information for the practicing clinician or the clinical development team, it is not sufficient to look only at influences of covariates on model parameters. Rather, the modeling results need to be carefully investigated in terms of clinically relevant measures.

A phase I/II study of pemetrexed and vinorelbine in patients with non-small cell lung cancer.

PURPOSE: Pemetrexed and vinorelbine are active antineoplastic agents in non-small cell lung cancer (NSCLC). Phase I objectives include maximum tolerated dose (MTD) and recommended phase II dose determination, and pharmacokinetics of the pemetrexed-vinorelbine doublet in locally advanced or metastatic solid tumor patients (pts). Phase II objectives include tumor response evaluation, efficacy, and toxicity for first-line treatment of advanced NSCLC. EXPERIMENTAL DESIGN: Phase I pts received pemetrexed (day 1, 300-700 mg/m2) and vinorelbine (days 1 and 8, 15-30 mg/m2) every 21 days. Pharmacokinetics determined at cycle 1. Beginning with dose-level 3, folic acid and Vitamin B12 supplementation were given. RESULTS: Thirty-one phase I pts were enrolled. MTD was pemetrexed 700 mg/m2 and vinorelbine 30 mg/m2; and recommended phase II dose was pemetrexed 500 mg/m2 and vinorelbine 30 mg/m2. When administered in combination, pemetrexed and vinorelbine pharmacokinetics were consistent with single-agent administration. Thirty-seven (36 chemonaive) phase II NSCLC pts received pemetrexed-vinorelbine. Evaluable tumor response was 40%, with intent-to-treat 38%. One drug-related death occurred from febrile neutropenia with Staphylococcal infection. Grade 3/4 hematologic toxicities were neutropenia (65%) and febrile neutropenia (11%), while prevalent grade 3/4 non-hematologic toxicity was fatigue (27%). CONCLUSION: The pemetrexed-vinorelbine combination is well tolerated and shows activity as first-line treatment in advanced NSCLC patients.