Evaluation of mycophenolic acid exposure in a patient with immune-related hepatotoxicity caused by nivolumab and ipilimumab therapy for malignant melanoma: a case report.

BACKGROUND: Guidelines such as the National Comprehensive Cancer Network recommend mycophenolate mofetil (MMF) for the treatment of severe steroid-refractory immune-related hepatotoxicity. Mycophenolic acid (MPA) is an active form of MMF that suppresses T- and B-lymphocyte proliferation and immune-related adverse events caused by immune checkpoint inhibitors. MPA has a narrow therapeutic range (37-70 µg·h/mL) and overexposure increases the risk of leukopenia in transplantation. However, the optimal use of MMF in oncology has not yet been established; thus, monitoring plasma MPA concentrations is necessary to avoid excessive immunosuppression in oncology practice. CASE PRESENTATION: We evaluated plasma MPA concentration in a 75-year-old man with immune-related hepatotoxicity following nivolumab and ipilimumab combination therapy for malignant melanoma. The patient developed severe hepatotoxicity after immunotherapy, and immunosuppressant therapy with corticosteroids was initiated. The patient then developed steroid-refractory immune-related hepatotoxicity; therefore, MMF (1,000 mg twice daily) was co-administered. Seven days after the administration of MMF, the plasma MPA concentration was measured using an enzyme multiplied immunoassay technique. The area under the plasma concentration-time curve for MPA from 0 to 12 h was 41.0 µg·h/mL, and the same dose of MMF was continued. Grade 2 lymphocytopenia, which could be attributed to MMF, was observed during the administration period. Unfortunately, the patient was infected with SARS-CoV-2 and died from respiratory failure. CONCLUSION: Our patient did not exceed the upper limit of MPA levels as an index of the onset of side effects of kidney transplantation and achieved rapid improvement in liver function. Prompt initiation of MMF after assessment of the steroid effect leads to adequate MPA exposure. Therapeutic drug monitoring should be considered when MMF is administered, to avoid overexposure.

Overnight fasting before lapatinib administration to breast cancer patients leads to reduced toxicity compared with nighttime dosing: a retrospective cohort study from a randomized clinical trial.

BACKGROUND: The bioavailability of lapatinib is affected by food, even following the 1 hour fast recommended by the package insert. We hypothesized that overnight fasting would minimize food-drug interactions. Here, we investigated if lapatinib administration timing is associated with its tolerability, efficacy, and pharmacokinetics. METHODS: This is a retrospective cohort study utilizing the medical records of patients enrolled in the JBCRG-16/Neo-LaTH randomized phase 2 trial for breast cancer patients treated with lapatinib. Lapatinib administration timing was divided into three groups: before breakfast (BB), between meals (BM), and at bedtime (AB). Side effects (SE), treatment discontinuation rate (TDR), relative dose intensity (RDI), pathological complete response (pCR) rate, and lapatinib serum trough concentration were compared between groups. RESULTS: About 140 patients were included in this study: BB 15, BM 51, and AB 74. A reduced risk of diarrhea {adjusted hazard ratio (HR), 0.51, 95% confidence interval (CI), 0.27-0.89, p = 0.018}, and rash {adjusted HR, 0.37; 95% CI, 0.17-0.70, p = 0.002} was seen in BB versus AB. Fewer patients with low RDI (< 0.85/<0.6) were in the BB group (BB 13% / 0%, BM 22% / 3.9%, AB 24% / 14%, p = 0.70 / 0.11). pCR was not diminished (p = 0.75). BB group had the lowest serum lapatinib concentration and variability (mean ±SD were 0.35 ± 0.15, 0.65 ± 0.32, 0.96 ± 0.43 µg/ml). CONCLUSIONS: Compared to bedtime administration, lapatinib administration after overnight fasting reduces its toxicity without diminishing its therapeutic efficacy.

Effects of Proton Pump Inhibitor Coadministration on the Plasma Concentration of Erlotinib in Patients With Non-Small Cell Lung Cancer.

BACKGROUND: Erlotinib is used for treating non-small cell lung cancer (NSCLC). Intestinal absorption of erlotinib is impaired under gastric pH elevation; therefore, coadministration of gastric acid suppressants may provide lower blood concentration of erlotinib. We investigated the effects of erlotinib coadministration with proton pump inhibitors (PPIs) and histamine H2 receptor blockers (H2RBs) on the plasma concentration of erlotinib and erlotinib-induced adverse reaction in patients with NSCLC. METHODS: Forty-two patients receiving erlotinib therapy for NSCLC were recruited for this study. Association of adverse reactions (rash and diarrhea) with plasma concentration of erlotinib was examined. Plasma concentration-to-dose (C/D) ratios and oral clearance (CL/F), which was estimated by population pharmacokinetic analysis of plasma concentrations of erlotinib, were compared among 3 patient groups: without coadministration of gastric acid suppressants (control group), with coadministration of PPI (PPI group), and coadministration of H2RB (H2RB group). RESULTS: Patients with grade ≥2 rash had higher plasma concentrations of erlotinib compared with those with grade ≤1 [1.02 (0.43-2.60) versus 0.67 (0.10-1.85) mcg/mL, P < 0.01]. The C/D ratios of erlotinib in the PPI and H2RB groups were lower than that in the control group [0.39 (0.08-0.76) and 0.48 (0.33-0.81) versus 0.51 (0.28-1.28) mcg·mL·mg·kg], where statistical significance was observed between PPI and control groups (P < 0.05). The population pharmacokinetic estimated oral CL/F in the PPI and H2RB groups were higher than that in the control group [5.55 (3.36-14.52) and 4.82 (2.08-6.32) versus 3.95 (2.01-10.44) L/h], where statistical significance was observed between PPI and control groups (P < 0.05). CONCLUSIONS: Plasma concentrations of erlotinib in patients under coadministration of gastric acid suppressants were lower than those without gastric acid suppressants through drug interaction, suppressing the intestinal absorption of erlotinib. The magnitude of this drug interaction was more pronounced in the coadministration of PPI compared with H2RB.

A Simple High-Performance Liquid Chromatography for Determining Lapatinib and Erlotinib in Human Plasma.

BACKGROUND: Lapatinib and erlotinib are used for cancer treatment, showing large interindividual variability. Therapeutic drug monitoring may be useful for assessing the clinical outcomes and adverse events. A simple high-performance liquid chromatography UV method was developed for the determination of lapatinib and erlotinib in human plasma. METHODS: An aliquot of plasma sample spiked with internal standard was treated with acetonitrile to precipitate the proteins. Lapatinib and erlotinib were separated on an octadecylsilyl silica gel column using a mobile phase consisting of acetonitrile, methanol, water, and trifluoroacetic acid (26:26:48:0.1) pumped at a flow rate of 1.0 mL/min. The detection wavelength was set at 316 nm. RESULTS: The calibration curves for lapatinib and erlotinib were linear (r = 0.9999) in the range of 0.125-8.00 mcg/mL. The extraction recoveries for both lapatinib and erlotinib at the plasma concentration of 0.125-8.00 mcg/mL were higher than 89.9% with coefficients of variation less than 3.5%. The coefficients of variation for intraday and interday assays of lapatinib and erlotinib were less than 5.1% and 6.1%, respectively. CONCLUSIONS: The present method can be used for blood concentration monitoring for lapatinib or erlotinib in exactly the same conditions.

Drug interaction between erlotinib and phenytoin for brain metastases in a patient with nonsmall cell lung cancer.

Erlotinib, a substrate drug metabolized by the CYP3A4 enzyme, is an epidermal growth factor receptor tyrosine kinase inhibitor used to treat nonsmall cell lung cancer (NSCLC). Concomitant use of erlotinib and the antiepileptic drug phenytoin, an inducer of CYP3A4, may result in a drug-drug interaction accompanied by changes in the blood concentrations of both drugs. We determined the blood concentration of each drug to confirm the interaction between phenytoin and erlotinib in a case of NSCLC with brain metastases. The phenytoin blood concentration (8.2-10.0µg/mL) gradually increased 3-fold (to 24.2µg/mL) 7 months after the start of erlotinib (150mg/d) co-administration. The erlotinib blood concentration which was maintained at 0.15-0.37µg/mL under phenytoin co-administration, increased 12-fold (to 1.77µg/mL) after the stoppage of phenytoin co-administration. The present case revealed that blood phenytoin increased and blood erlotinib decreased subsequent to the interaction of the 2 drugs in the CYP3A4 metabolic enzyme system.

Expression of acetoacetyl-CoA synthetase, a novel cytosolic ketone body-utilizing enzyme, in human brain.

Acetoacetyl-CoA synthetase (AACS, acetoacetate-CoA ligase, EC 6.2.1.16) is a ketone body-utilizing enzyme, the physiological role of which remains unclear yet in mammals, particularly has never been studied in human. In order to investigate the tissue distribution of AACS in human, cDNA encoding AACS was isolated from HepG2 cells. Amino acid sequence of human AACS deduced from the open reading frame showed high homology (89.3%) with that of rat AACS and much less homology (43.7%) with that of bacterial AACS. The expression level of the AACS mRNA was high in kidney, heart and brain, but low in liver, and the expression profile of AACS in the human brain was quite similar to that of 3-hydroxy-3-methylglutaryl-CoA reductase.

Effects of streptozotocin-induced diabetes on acetoacetyl-CoA synthetase activity in rats.

In order to investigate the physiological role of acetoacetyl-CoA synthetase (acetoacetate-CoA ligase, EC 6.2.1.16), a cytosolic acetoacetate-activating enzyme, effects of streptozotocin (STZ)-induced diabetes on the enzyme activity was investigated in rats. At 72 hr of the STZ administration (80 mg/kg body weight, injected intravenously), hepatic enzyme specific activity decreased to 23% of its initial activity. However, the enzyme activities in non-hepatic tissues were not significantly affected by the STZ treatment. Feeding of rats with both 4% cholestyramine and 0.4% pravastatin for 3 days remarkably increased the hepatic acetoacetyl-CoA synthetase activity and decreased the plasma ketone bodies level in the diabetic rats. These results suggest that acetoacetyl-CoA synthetase has important roles in the regulation of ketone body utilization in rat liver and that these hypocholesterolemic agents have the ability to remedy the impaired utilization of ketone bodies under the diabetic condition.