Impact of Sotorasib on the Pharmacokinetics and Pharmacodynamics of Metformin, a MATE1/2K Substrate, in Healthy Subjects.

BACKGROUND AND OBJECTIVE: The objectives of this study were to evaluate the effect of sotorasib on metformin pharmacokinetics and pharmacodynamics and the effect of metformin on sotorasib pharmacokinetics in healthy subjects. Sotorasib is an oral, small molecule inhibitor of the Kirsten rat sarcoma oncogene homolog (KRAS) G12C mutant protein (KRASG12C) protein approved by the U.S. Food and Drug Administration in 2021 for the treatment of KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) in adults who have received at least one prior systemic therapy METHODS: This was a phase I, single-center, open-label, three-period, fixed-sequence study. Subjects received single oral doses of metformin 850 mg, sotorasib 960 mg, and metformin 850 mg with sotorasib 960 mg. Urine and plasma were collected and assayed for metformin and sotorasib pharmacokinetics. Blood glucose was also measured for metformin pharmacodynamics. In addition, an in vitro study was conducted to determine whether sotorasib was an inhibitor of MATE1/2K or OCT2 transport. RESULTS: Geometric least-squares mean ratio of sotorasib area under the concentration-time curve from time 0 to infinity and peak plasma concentration were 0.910 and 0.812, respectively, when sotorasib was coadministered with metformin compared with administration of sotorasib alone. Geometric least-squares mean ratio of metformin area under the concentration-time curve from time 0 to infinity and peak plasma concentration were 0.99 and 1.00, respectively, when comparing metformin coadministered with sotorasib to metformin alone. Geometric mean estimates of serum glucose area under the concentration-time curve from time 0 to 2 h following metformin alone, sotorasib alone, and metformin with sotorasib were 179, 222, and 194, respectively. CONCLUSIONS: These results demonstrated that coadministration of metformin with sotorasib does not impact sotorasib exposure to a clinically significant extent. Coadministration of sotorasib with metformin does not affect metformin exposure or its antihyperglycemic effect, in contrast to the inhibitory effect observed in vitro. Doses of sotorasib 960 mg and metformin 850 mg were safe and well tolerated when coadministered to healthy subjects.

Validation of an LC-MS/MS method for the determination of sotorasib, a KRASG12C inhibitor, in human plasma.

Background: Sotorasib (AMG 510) is a first-in-class KRASG12C inhibitor that received accelerated US FDA approval in 2021 for the treatment of patients with KRASG12C-mutated locally advanced or metastatic non-small-cell lung cancer. Method: An LC-MS/MS method was developed and validated for the determination of sotorasib in human plasma to support clinical development studies. Samples were prepared using protein precipitation and analyzed by LC-MS/MS using gradient elution with a calibration standard curve range of 10.0-10,000 ng/ml. Stable isotope labeled [13C, D3]-sotorasib was used as an internal standard. Results & conclusion: The method fully met FDA guidelines for all validation parameters, including precision, accuracy, selectivity, matrix effect, recovery and stability and has been extensively used to support multiple clinical studies.

Absorption, metabolism and excretion of [14C]-sotorasib in healthy male subjects: characterization of metabolites and a minor albumin-sotorasib conjugate.

PURPOSE: The objectives of this study were to characterize the absorption, metabolism, and excretion of sotorasib and determine the metabolites present in plasma, urine, and feces in healthy male subjects following a single oral 720 mg dose containing approximately 1 µCi of [14C]-sotorasib. METHODS: Urine, feces, and plasma were collected post-dose and assayed for total radioactivity and profiled for sotorasib metabolites. Urine and plasma were also assayed for sotorasib pharmacokinetics. In addition, in vitro studies were performed to determine the enzymes responsible for formation of major circulating metabolites and protein adducts in human plasma. RESULTS: Sotorasib was rapidly absorbed, with a median time to peak concentration of 0.75 h. Mean t1/2,z of plasma sotorasib, whole blood total radioactivity, and plasma total radioactivity were 6.35, 174, and 128 h, respectively. The geometric mean cumulative recovery was 80.6%; the majority was excreted in feces (74.4%) with a low percentage excreted in urine (5.81%). M10, sotorasib, and M24 were present at 31.6%, 22.2%, and 13.7% of total radioactivity in plasma extracts, respectively. M10 and sotorasib were present at < 5% of administered radioactivity in urine, while only unchanged sotorasib, at 53% of administered radioactivity, was identified in feces. A sotorasib-albumin adduct was identified in plasma as a minor constituent, consistent with the observed radioactivity profile in plasma/blood. CONCLUSION: Sotorasib metabolism involves nonenzymatic glutathione conjugation, GGT-mediated hydrolysis of glutathione adduct, and direct CYP3A and CYP2C8-mediated oxidation. Elimination of sotorasib is predominantly fecal excretion, suggesting dose reduction is not necessary with renal impairment.

Intravenous and Intramuscular Allopregnanolone for Early Treatment of Status Epilepticus: Pharmacokinetics, Pharmacodynamics, and Safety in Dogs.

Allopregnanolone (ALLO) is a neurosteroid that modulates synaptic and extrasynaptic GABAA receptors. We hypothesize that ALLO may be useful as first-line treatment of status epilepticus (SE). Our objectives were to (1) characterize ALLO pharmacokinetics-pharmacodynamics PK-PD after intravenous (IV) and intramuscular (IM) administration and (2) compare IV and IM ALLO safety and tolerability. Three healthy dogs and two with a history of epilepsy were used. Single ALLO IV doses ranging from 1-6 mg/kg were infused over 5 minutes or injected IM. Blood samples, vital signs, and sedation assessment were collected up to 8 hours postdose. Intracranial EEG (iEEG) was continuously recorded in one dog. IV ALLO exhibited dose-proportional increases in exposure, which were associated with an increase in absolute power spectral density in all iEEG frequency bands. This relationship was best described by an indirect link PK-PD model where concentration-response was described by a sigmoidal maximum response (Emax) equation. Adverse events included site injection pain with higher IM volumes and ataxia and sedation associated with higher doses. IM administration exhibited incomplete absorption and volume-dependent bioavailability. Robust iEEG changes after IM administration were not observed. Based on PK-PD simulations, a 2 mg/kg dose infused over 5 minutes is predicted to achieve plasma concentrations above the EC50, but below those associated with heavy sedation. This study demonstrates that ALLO is safe and well tolerated when administered at 1-4 mg/kg IV and up to 2 mg/kg IM. The rapid onset of effect after IV infusion suggests that ALLO may be useful in the early treatment of SE. SIGNIFICANCE STATEMENT: The characterization of the pharmacokinetics and pharmacodynamics of allopregnanolone is essential in order to design clinical studies evaluating its effectiveness as an early treatment for status epilepticus in dogs and people. This study has proposed a target dose/therapeutic range for a clinical trial in canine status epilepticus.

Intravenous Topiramate: Pharmacokinetics in Dogs with Naturally Occurring Epilepsy.

RATIONALE: Barriers to developing treatments for human status epilepticus include the inadequacy of experimental animal models. In contrast, naturally occurring canine epilepsy is similar to the human condition and can serve as a platform to translate research from rodents to humans. The objectives of this study were to characterize the pharmacokinetics of an intravenous (IV) dose of topiramate (TPM) in dogs with epilepsy and evaluate its effect on intracranial electroencephalographic (iEEG) features. METHODS: Five dogs with naturally occurring epilepsy were used for this study. Three were getting at least one antiseizure drug as maintenance therapy including phenobarbital (PB). Four (ID 1-4) were used for the 10 mg/kg IV TPM + PO TPM study, and three (ID 3-5) were used for the 20 mg/kg IV TPM study. IV TPM was infused over 5 min at both doses. The animals were observed for vomiting, diarrhea, ataxia, and lethargy. Blood samples were collected at scheduled pre- and post-dose times. Plasma concentrations were measured using a validated high-performance liquid chromatography-mass spectrometry method. Non-compartmental and population compartmental modeling were performed (Phoenix WinNonLin and NLME) using plasma concentrations from all dogs in the study. iEEG was acquired in one dog. The difference between averaged iEEG energy levels at 15 min pre- and post-dose was assessed using a Kruskal-Wallis test. RESULTS: No adverse events were noted. TPM concentration-time profiles were best fit by a two compartment model. PB co-administration was associated with a 5.6-fold greater clearance and a ~4-fold shorter elimination half-life. iEEG data showed that TPM produced a significant energy increase at frequencies >4 Hz across all 16 electrodes within 15 min of dosing. Simulations suggested that dogs on an enzyme inducer would require 25 mg/kg, while dogs on non-inducing drugs would need 20 mg/kg to attain the target concentration (20-30 µg/mL) at 30 min post-dose. CONCLUSION: This study shows that IV TPM has a relatively rapid onset of action, loading doses appear safe, and the presence of PB necessitates a higher dose to attain targeted concentrations. Consequently, it is a good candidate for further evaluation for treatment of seizure emergencies in dogs and people.