If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ൒3 days, CTC Grade 4 neutropenia lasting ൒3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days. The ability of ALIMTA to be dialyzed is unknown. 11 DESCRIPTION Pemetrexed disodium heptahydrate has the chemical name L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H - pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate. It is a white to almost-white solid with a molecular formula of C 20H19N5Na2O6•7H 2O and a molecular weight of 597.49. The structural formula is as follows: ALIMTA is supplied as a sterile lyophilized powder for intravenous infusion available in single-dose vials. The product is a white to either light yellow or green-yellow lyophilized solid. Each 100-mg or 500-mg vial of ALIMTA contains pemetrexed disodium equivalent to 100 mg pemetrexed and 106 mg mannitol or 500 mg pemetrexed and 500 mg mannitol, respectively. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action ALIMTA, pemetrexed for injection, is a folate analog metabolic inhibitor that exerts its action by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS ), Protocol ADU-CL-02-v8Aduro Biotech, Inc. CRS-207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 950 0 12 dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltr ansferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers su ch as the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibito rs of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, is thought to occur to a lesser extent, in normal tissues. Polyglutamated metabolites are thought to have an increased intracellular half-life resulti ng in prolonged drug action in malignant cells. 12.2 Pharmacodynamics Preclinical studies have shown that pemetrexed inhibits the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052). Studies with the MSTO-211H mesothelioma cell line showed synergistic effects when pemetrexed was combined concurrently with cisplatin. Absolute neutrophil counts (ANC) following single-agent administration of ALIMTA to patients not receiving folic acid and vitamin B 12supplementation were characterized using population pharmacodynamic analyses. Severity of hematologic toxicity, as measured by the depth of the ANC nadir, correlates with the systemic exposure, or area under the curve (AUC) of pemetrexed. It w as also observed that lower ANC nadirs occurred in patients with elevated baseline cystathionine or homocysteine concentrations. Th e levels of these substances can be reduced by folic acid and vitamin B 12supplementation. There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles. Time to ANC nadir with pemetrexed systemic exposure (AUC), varied between 8 to 9.6 days over a range of exposures from 38.3 to 316.8 mcg• hr/mL. Return to baseline ANC occurred 4.2 to 7.5 days after the nadir over the same range of exposures. 12.3 PharmacokineticsAbsorption The pharmacokinetics of ALIMTA administered as a single-agent in doses ranging from 0.2 to 838 mg/m 2infused over a 10-minute period have been evaluated in 426 cancer patients with a variety of solid tumors. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (C max) increase proportionally with dose. The pharmacokinetics of pemetrexed do not change over multiple treatment cycles. Distribution Pemetrexed has a steady-state volume of distribution of 16.1 liter s. In vitro studies indicate that pemetrexed is approximately 81% bound to plasma proteins. Binding is not affected by degree of renal impairment.Metabolism and Excretion Pemetrexed is not metabolized to an appreciable extent a nd is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. The clearance decreases, and exposure (AUC) increases, as renal function decreases. The total systemic clearance of pemetrexed is 91.8 mL/min and the elimination half-life of pemetrexed is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min). The pharmacokinetics of pemetrexed in special populations were examined in about 400 patients in controlled and single arm studies. In vitro studies indicate that pemetrexed is a substrate of OAT3 (organic anion transporter 3), a transporter that may play a role in active secretion of pemetrexed. Effect of Age No effect of age on the pharmacokinetics of pemetrexed was observed over a range of 26 to 80 years. Effect of Gender The pharmacokinetics of pemetrexed were not different in male and female patients. Effect of Race The pharmacokinetics of pemetrexed were similar in Caucasians and patients of African descent. Insufficient data are available to compare pharmacokinetics for other ethnic groups.Effect of Hepatic Insufficiency There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed. However, studies of hepatically impaired patients have not been conducted [see Dosage and Administration (2.4) and Use in Specific Populations (8.6)] . Effect of Renal Insufficiency Pharmacokinetic analyses of pemetrexed included 127 patients with reduced renal function. Plasma clearance of pemetrexed decreases as renal function decreases, with a resultant increase in systemic exposure. Patients with creatinine clearances of 45, 50, and 80 mL/min had 65%, 54%, and 13% increases, respectively in pemetrexed total systemic exposure (AUC) compared to patients with creatinine clearance of 100 mL/min [see Warnings and Precautions (5.4) and Dosage and Administration (2.4)] . Effect of Third Space Fluid The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is not fully defined. A study of ALIMTA 500 mg/m 2was performed in 31 solid tumor patients with stable third space fluid (All but 2 of the 31 patients included in study had mild or moderate amounts of third space fluid). Moderate pleural effusion was defined in the study as less than 1/3 the way up on one side with obscuring of the entire hemidiaphragm. Moderate ascites was defined as that detectable on physical exam. The pemetrex ed plasma concentrations in these patients were comparable to those observed in previous clinical trials in patients without third space fluid collections. Thus, drainage of mild or moderate third space fluid collection prior to ALIMTA treatment should be consider ed, but is probably not necessary. The effect of severe third space fluid on pharmacokinetics is not known.Protocol ADU-CL-02-v8Aduro Biotech, Inc. CRS-207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 96 13 Effect of Ibuprofen Ibuprofen doses of 400 mg four times a day reduce pemetrexed’s clearance by about 20% (and increase AUC by 20%) in patients with normal renal function. The effect of greater doses of ibuprofen on pemetrexed pharmacokinetics is unknown [see Drug Interactions (7.1)] . Effect of Aspirin Aspirin, administered in low to moderate doses (325 mg every 6 hours), does not affect the pharmacokinetics of pemetrexed. The effect of greater doses of aspirin on pemetrexed pharmacokinetics is unknown. Effect of Cisplatin Cisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed.Effect of Vitamins Coadministration of oral folic acid or intramuscular vitamin B 12does not affect the pharmacokinetics of pemetrexed. Drugs Metabolized by Cytochrome P450 Enzymes Results from in vitro studies with human liver microsomes predict that pemetrexed would not cause clinically significant inhibition of metabolic clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinoge nesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2basis) resulted in reduced fertility, hypospermia, and testicular atrophy. 14 CLINICAL STUDIES 14.1 Non-Small Cell Lung Cancer (NSCLC) - Combination with Cisplatin A multi-center, randomized, open-label study in 1725 chemonaive patients with Stage IIIb/IV NSCLC was conducted to compare the overall survival following treatment with ALIMTA in combination with cisplatin (AC) versus gemcitabine in combination with cisplatin (GC). ALIMTA was administered intravenously over 10 minutes at a dose of 500 mg/m2with cisplatin administered intravenously at a dose of 75 mg/m2after ALIMTA administration, on Day 1 of each 21-day cycle. Gemcitabine was administered at a dose of 1250 mg/m2on Day 1 and Day 8, and cisplatin was administered intravenously at a dose of 75 mg/m2after administration of gemcitabine, on Day 1 of each 21-day cycle. Treatment was administered up to a total of 6 cycles, and patients in both treatment arms received folic acid, vitamin B 12, and dexamethasone [see Dosage and Administration (2.3)] . Patient demographics of the intent to treat (ITT) popula tion are shown in Table 9.