Population pharmacokinetics of the GIP/GLP receptor agonist tirzepatide.

Tirzepatide is a first-in-class glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved as for the treatment of type 2 diabetes mellitus. A population-based pharmacokinetic (PK) model was developed from 19 pooled studies. Tirzepatide pharmacokinetics were well-described by a two-compartment model with first order absorption and elimination. The tirzepatide population PK model utilized a semimechanistic allometry model to describe the relationship between body size and tirzepatide PK. The half-life of tirzepatide was ~5 days and enabled sustained exposure with once-weekly subcutaneous dosing. The covariate analysis suggested that adjustment of the dose regimen based on demographics or subpopulations was unnecessary. The tirzepatide PK model can be used to predict tirzepatide exposure for various scenarios or populations.

Model-based simulation of glycaemic effect and body weight loss when switching from semaglutide or dulaglutide to once weekly tirzepatide.

OBJECTIVE: To evaluate the efficacy endpoints of HbA1c and body weight loss after switching from the GLP-1 receptor agonists, semaglutide or dulaglutide, to treatment with the GIP/GLP-1 receptor agonist (RA) tirzepatide. METHODS: Models were developed and validated to describe the HbA1c and weight loss time course for semaglutide (SUSTAIN 1-10), dulaglutide (AWARD-11) and tirzepatide (SURPASS 1-5, phase 3 global T2D program). The impact of switching from once weekly GLP-1 RAs to tirzepatide was described by simulating the efficacy time course. Semaglutide and dulaglutide doses were escalated in accordance with their respective labels. RESULTS: Model-predicted mean decreases from baseline in HbA1c and body weight for semaglutide 0.5 mg, 1 mg, and 2 mg were 1.22 to 1.79% and 3.62 to 6.87 kg respectively, at Week 26. Model-predicted mean decreases from baseline in HbA1c and body weight for dulaglutide 1.5 mg, 3 mg and 4.5 mg were 1.53 to 1.84% and 2.55 to 3.71 kg respectively, at Week 26. After switching to tirzepatide 5, 10 and 15 mg HbA1c reductions were predicted to range between 1.95 to 2.46% and body weight reductions between 6.50 to 12.1 kg by Week 66. CONCLUSION: In this model-based simulation, switching from approved maintenance doses of semaglutide or dulaglutide to tirzepatide, even at the lowest approved maintenance dose of 5 mg, showed the potential to further improve HbA1c and body weight reductions.

Type 2 diabetes is a disease of elevated blood sugar levels. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a type of medication used to treat type 2 diabetes that work on GLP-1 receptors in the body. Semaglutide and dulaglutide are examples of GLP-1 RAs, which lower blood sugar and body weight. Tirzepatide is a newer medication, which works on both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors. It reduces blood sugar and body weight in people living with type 2 diabetes. Healthcare professionals and patients are interested in how switching medication from semaglutide or dulaglutide to tirzepatide might change blood glucose levels and body weight. However, because tirzepatide is a newer medication, there is not much information available on this aspect. Data from clinical trials of these medications were used to predict the effects of switching from semaglutide or dulaglutide to tirzepatide. These model-based simulations showed that switching to tirzepatide may further reduce HbA1c (a measure of blood sugar) and body weight. This may provide useful information to healthcare professionals and patients when making decisions about treatment with these medications.

Tirzepatide Immunogenicity on Pharmacokinetics, Efficacy, and Safety: Analysis of Data From Phase 3 Studies.

CONTEXT: Antidrug antibodies (ADA) can potentially affect drug pharmacokinetics, safety, and efficacy. OBJECTIVE: This work aimed to evaluate treatment-emergent (TE) ADA in tirzepatide (TZP)-treated participants across 7 phase 3 trials and their potential effect on pharmacokinetics, efficacy, and safety. METHODS: ADA were assessed at baseline and throughout the study until end point, defined as week 40 (SURPASS-1, -2, and -5) or week 52 (SURPASS-3, -4, Japan-Mono, and Japan-Combo). Samples for ADA characterization were collected at SURPASS trial sites. Participants included ADA-evaluable TZP-treated patients with type 2 diabetes (N = 5025). Interventions included TZP 5, 10, or 15 mg. ADA were detected and characterized for their ability to cross-react with native glucose-dependent insulinotropic polypeptide (nGIP) and glucagon-like peptide-1 (nGLP-1), neutralize tirzepatide activity on GIP and GLP-1 receptors, and neutralize nGIP and nGLP-1. RESULTS: TE ADA developed in 51.1% of tirzepatide-treated patients. Proportions were similar across dose groups. Maximum ADA titers ranged from 1:20 to 1: 81 920 among TE ADA+ patients. Neutralizing antibodies (NAb) against TZP activity on GIP and GLP-1 receptors were observed in 1.9% and 2.1% of patients, respectively. Less than 1.0% of patients had cross-reactive NAb against nGIP or nGLP-1. TE ADA status, ADA titer, and NAb status had no effect on the pharmacokinetics or efficacy of TZP. More TE ADA+ patients experienced hypersensitivity reactions or injection site reactions than TE ADA- patients. The majority of hypersensitivity and injection site reactions were nonserious and nonsevere, and most events occurred and/or resolved irrespective of TE ADA status or titer. CONCLUSION: Immunogenicity did not affect TZP pharmacokinetics or efficacy. The majority of hypersensitivity or injection site reactions experienced by TE ADA+ patients were mild to moderate in severity.

Prediction of renal transporter mediated drug-drug interactions for pemetrexed using physiologically based pharmacokinetic modeling.

Pemetrexed, an anionic anticancer drug with a narrow therapeutic index, is eliminated mainly by active renal tubular secretion. The in vitro to in vivo extrapolation approach used in this work was developed to predict possible drug-drug interactions (DDIs) that may occur after coadministration of pemetrexed and nonsteroidal anti-inflammatory drugs (NSAIDs), and it included in vitro assays, risk assessment models, and physiologically based pharmacokinetic (PBPK) models. The pemetrexed transport and its inhibition parameters by several NSAIDs were quantified using HEK-PEAK cells expressing organic anion transporter (OAT) 3 or OAT4. The NSAIDs were ranked according to their DDI index, calculated as the ratio of their maximum unbound concentration in plasma over the concentration inhibiting 50% (IC50) of active pemetrexed transport. A PBPK model for ibuprofen, the NSAID with the highest DDI index, was built incorporating active renal secretion in Simcyp Simulator. The bottom-up model for pemetrexed underpredicted the clearance by 2-fold. The model we built using a scaling factor of 5.3 for the maximal uptake rate (Vmax) of OAT3, which estimated using plasma concentration profiles from patients given a 10-minute infusion of 500 mg/m(2) of pemetrexed supplemented with folic acid and vitamin B12, recovered the clinical data adequately. The observed/predicted increases in Cmax and the area under the plasma-concentration time curve (AUC0-inf) of pemetrexed when ibuprofen was coadministered were 1.1 and 1.0, respectively. The coadministration of all other NSAIDs was predicted to have no significant impact on the AUC0-inf based on their DDI indexes. The PBPK model reasonably reproduced pemetrexed concentration time profiles in cancer patients and its interaction with ibuprofen.

A phase I study of pemetrexed in patients with relapsed or refractory acute leukemia.

PURPOSE: To investigate the toxicity profile, activity, pharmacokinetics, and pharmacodynamics of pemetrexed in leukemia. PATIENTS AND METHODS: Patients with refractory or relapsed acute leukemia were eligible. A phase I 3+3 design was implemented. Pemetrexed was infused intravenously (IV) over 25 min with vitamin supplementation. Courses were repeated every 3 to 4 weeks according to toxicity and efficacy. The starting dose of 900 mg/m² was escalated by approximately 33% until the dose-limiting toxicity (DLT) was determined. RESULTS: Twenty patients with acute myeloid (AML) or lymphocytic (ALL) leukemia received therapy. The main non-hematologic adverse event was liver dysfunction at several dose levels, including 2 DLTs at 3,600 mg/m². One patient with ALL (3,600 mg/m² dose level) achieved a partial response. Pemetrexed pharmacokinetics were linear with escalated dosing. Elevated plasma deoxyuridine was observed in a subset of patients following pemetrexed infusion, but was not correlated with dose levels. Changes in the nucleotide pools of circulating mononuclear cells were observed, but were variable. CONCLUSIONS: The recommended phase II dose of pemetrexed for future leukemia studies is 2,700 mg/m(2) IV over 25 min every 3 to 4 weeks with vitamin supplementation. Deoxyuridine levels did not increase with increasing pemetrexed dose, suggesting pemetrexed inhibition of thymidylate synthase (TS) may be saturated by the 900 mg/m² dose level. However, no firm conclusion can be made regarding TS saturation in tumor cells. While tolerable, pemetrexed monotherapy had limited activity in this highly refractory population. Exploration of pemetrexed in combination with other active agents in leukemia is a reasonable future endeavor.

Pemetrexed safety and pharmacokinetics in patients with third-space fluid.

PURPOSE: Pemetrexed is established as first-line treatment with cisplatin for malignant pleural mesothelioma and advanced nonsquamous non-small-cell lung cancer (NSCLC) and as single-agent second-line treatment for nonsquamous NSCLC. Because the structure and pharmacokinetics of pemetrexed are similar to those of methotrexate, and methotrexate is associated with severe toxicity in patients with third-space fluid (TSF), the safety of pemetrexed in patients with TSF was evaluated. EXPERIMENTAL DESIGN: Patients with TSF (pleural effusions, ascites) and relapsed, stage III/IV NSCLC or malignant pleural/peritoneal mesothelioma were treated with pemetrexed (500 mg/m2) on day 1 of each 21-day cycle. TSF was drained at any time only if clinically indicated. Plasma samples were collected during cycles 1 and 2 to compare pemetrexed concentrations with reference data from patients without TSF. RESULTS: Thirty-one patients with TSF received 123 pemetrexed doses (median, 4 cycles per patient; range, 1-11; mean dose intensity, 97.5%). Seven grade 3/4 drug-related toxicities, including four hematologic, were reported; there were no treatment-related deaths. There was no correlation between TSF amount and type, number, and sequelae of toxicities. Pemetrexed plasma concentrations were within the range of those in patients without TSF. Pemetrexed clearance and central volume of distribution were not statistically different between patients with and without TSF. CONCLUSIONS: No clinically relevant alterations of pemetrexed pharmacokinetics occurred in patients with TSF. Pemetrexed was well tolerated; toxicities were expected and manageable. The standard pemetrexed dose recommendations were adequate for patients with TSF in this study. These data suggest that draining TSF before administering pemetrexed is unnecessary.

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 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.