Effects of Rifampicin On Pyrotinib Maleate Pharmacokinetics In Healthy Subjects

Purpose: Pyrotinib (PTN) is primarily metabolized by cytochrome P450 (CYP)3A4 isozyme. Rifampicin (RIF) is a strong CYP3A4 inducer. Thus, the effect of oral RIF on PTN pharmacokinetics (PK) was evaluated to provide dose recommendation when co-administered.Method: This phase I, open-label study investigated the effects of steady-state RIF administration on single-dose PK of PTN, in 18 healthy participants who received PTN 400 mg single doses on days 1 and 13, and were administrated with RIF 600 mg qd on days 6-16. Each dose for RIF was administrated on an empty stomach, PTN were administrated orally in the morning 30 min after the start of the standard meal. Serial PK samples for PTN were collected on day 1 and day 13. Plasma PTN PK parameters were determined with non-compartmental analysis. Geometric least-squares mean ratios (GMRs) and 90% confidence intervals (CIs) were generated by the mixed-effected model for within-subject treatment comparisons. Safety assessments were performed throughout the study.Results: Eighteen subjects were enrolled and 15 completed the study. RIF significantly reduced PTN exposure: GMRs (90 % CI) for PTN + RIF versus PTN alone were 0.04 (0.034,0.049), 0.04 (0.037,0.054), and 0.11 (0.09,0.124) for area under the curve from time zero to time of last quantifiable concentration (AUC0-t), area under the curve from time zero to infinity (AUC0-∞ ), and maximum observed plasma concentration(Cmax), respectively. PTN alone and co-administered with RIF was well tolerated.Conclusion: Concurrent administration of PTN and RIF was associated with significantly decreased systemic exposure to PTN. The findings suggest that concomitant strong CYP3A4 inducers should be avoided during PTN treatment. Concurrent administration of PTN and RIF was well tolerated.

In vitro and clinical investigations to determine the drug-drug interaction potential of entrectinib, a small molecule inhibitor of neurotrophic tyrosine receptor kinase (NTRK)

Background Entrectinib is a CNS-active, potent inhibitor of tyrosine receptor kinases A/B/C, ROS1 and anaplastic lymphoma kinase approved for use in patients with solid tumors. We describe the in vitro and clinical studies investigating potential entrectinib drug-drug interactions. Methods In vitro studies with human biomaterials assessed the enzymes involved in entrectinib metabolism, and whether entrectinib modulates the activity of the major cytochrome P450 (CYP) enzymes or drug transporter P-glycoprotein. Clinical studies investigated the effect of a strong CYP3A4 inhibitor (itraconazole) and inducer (rifampin) on single-dose entrectinib pharmacokinetics. The effect of entrectinib on sensitive probe substrates for CYP3A4 (midazolam) and P-glycoprotein (digoxin) were also investigated. Results Entrectinib is primarily metabolized by CYP3A4. In vitro, entrectinib is a CYP3A4/5 inhibitor (IC50 2 μM) and a weak CYP3A4 inducer. Entrectinib inhibited P-glycoprotein (IC50 1.33 μM) but is a poor substrate. In healthy subjects, itraconazole increased entrectinib Cmax and AUC by 73% and 504%, respectively, and rifampin decreased entrectinib Cmax and AUC by 56% and 77%, respectively. Single dose entrectinib did not affect midazolam AUC, although Cmax decreased by 34%. Multiple dose entrectinib increased midazolam AUC by 50% and decreased Cmax by 21%. Single dose entrectinib increased digoxin AUC and Cmax by 18% and 28%, respectively, but did not affect digoxin renal clearance. Conclusions Entrectinib is a CYP3A4 substrate and is sensitive to the effects of coadministered moderate/strong CYP3A4 inhibitors and strong inducers, and requires dose adjustment. Entrectinib is a weak inhibitor of CYP3A4 and P-glycoprotein and no dose adjustments are required with CYP3A4/P- glycoprotein substrates.Registration Number (Study 2) NCT03330990 (first posted online November 6, 2017) As studies 1 and 3 are phase 1 trials in healthy subjects, they are not required to be registered.

PCSK9 Inhibitors for the Management of Mitotane-Induced Hypercholesterolemia in Adrenocortical Carcinoma

Background: After surgical resection in adrenocortical carcinoma (ACC), mitotane is often used as adjuvant therapy. However, mitotane can cause adverse effects, such as inducing hypercholesterolemia by stimulating HMG-CoA reductase. In addition, mitotane is a strong CYP3A4 inducer which presents a challenge with statins, such as lovastatin, simvastatin, and atorvastatin. We present a case using a PCSK9 inhibitor in mitotane-induced hypercholesterolemia which was refractory to the maximum dose of rosuvastatin. Clinical Case: A laparoscopic left adrenalectomy was performed on a 45-year old female with Stage 3 (T3, NX, M0) ACC (4.5 x 3.4 x 3.2 cm). Her ACC was determined to be high grade with a mitotic rate 20/50 HPF and Ki-67 of 18.7% with lymphovascular invasion and tumor invasion of periadrenal adipose tissue. Following surgical resection, she started adjuvant therapy mitotane and oral hydrocortisone replacement, as well as 6 weeks of radiation therapy. Prior to starting mitotane, her LDL-C was 133 mg/dL (normal range <130 mg/dL) and treated with simvastatin 40 mg daily. A drug interaction was identified between simvastatin and mitotane, with mitotane reducing effects of simvastatin via CYP3A4 induction, so rosuvastatin 10 mg daily was started instead. A trial of combination rosuvastatin and ezetimibe was used; however, patient discontinued ezetimibe due to reported side effects. As the dose of mitotane increased to achieve a blood concentration of 14–20 mcg/mL, LDL-C simultaneously increased along with a corresponding dose increase of rosuvastatin. While being on mitotane 2 g daily and rosuvastatin 40 mg daily, her lipids peaked with LDL-C 219 mg/dL. The decision was made to start evolocumab administered as 140 mg subcutaneously every 2 weeks in addition to rosuvastatin 40 mg daily. After 4 months of therapy with combination evolocumab and rosuvastatin, her LDL-C decreased to 111 mg/dL, a 49% reduction, while achieving a mitotane concentration of 13 mcg/mL using 4 g daily. Conclusion: Utilizing a PCSK9 inhibitor, such as evolocumab, allows the dose of mitotane to be increased to achieve a therapeutic level while maintaining adequate control of cholesterol. With options for management of mitotane-induced hypercholesterolemia being limited, off-label use of a PCSK9 inhibitor can be justified clinically as moderate LDL-C reduction has also been shown in a prior published case report (1). Evolocumab is a well-tolerated subcutaneous injection, and should be considered for patients with resistant hypercholesterolemia while on mitotane. References: (1) Tsakiridou ED, Liberopoulos E, Giotaki Z, et al. Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor use in the management of resistant hypercholesterolemia induced by mitotane treatment for adrenocortical cancer. J Clin Lipidol. 2018;12(3):826–829.

THU0210 EARLY DISCONTINUATION OF TOFACITINIB IN PATIENTS WITH RHEUMATOID ARTHRITIS CO-TREATED WITH RIFAMPIN FOR LATENT TUBERCULOSIS: RESULTS FROM THE REAL-WORLD DATA

Background:Rheumatoid arthritis (RA) patients need to undergo screening and receive treatment for latent tuberculosis infection (LTBI) before starting tofacitinib, which is primarily metabolized by cytochrome P450 (CYP) 3A4. Among chemoprophylactic agents, rifampin is known to be a potent CYP3A4 inducer; therefore, it is expected to decrease the efficacy of tofacitinib. However, tofacitinib and rifampin have been co-administered practically because of the short duration of chemoprophylaxis.Objectives:The aim of this study was to determine the efficacy of tofacitinib on co-administration with rifampin.Methods:Biologic-naïve RA patients treated with tofacitinib were selected, and electronic medical reports were reviewed retrospectively. All patients underwent screening for LTBI before starting tofacitinib, and patients with positive results were treated to prevent progression to active tuberculosis. To evaluate the efficacy of tofacitinib with or without rifampin, the discontinuation rates of tofacitinib were examined during the first 6 months. Kaplan–Meier analysis was used to construct cumulative discontinuation curves, and comparisons were performed using the log-rank test.Results:Among 81 patients who started tofacitinib, 21 (25.9%) were LTBI-positive and 18 (22.2%) were administered rifampin concomitantly with tofacitinib. The median follow-up time was 6 months in both patients who received rifampin (interquartile range [IQR] 2.21, 6.00) and those who did not receive rifampin (IQR 5.97, 6.00) (p = 0.083). There were no significant differences between patients who received rifampin and those who did not receive rifampin in all baseline characteristics, except the swollen joint count (3.00 [1.75, 5.25] vs. 5.00 [4.00, 7.00]; p = 0.025), at the time of starting tofacitinib. In patients who received rifampin at the time of starting tofacitinib, the mean duration of co-administration was 47.00 ± 23.54 days (median 56; IQR 28.75, 59.00). During follow-up, 14 of the 81 patients (17.3%) discontinued tofacitinib. As shown in the Figures 1 and 2, the discontinuation rate of tofacitinib within the first 6 months was significantly higher among patients who received rifampin for LTBI than among those who did not receive rifampin (lack of efficacy: 24.7% vs. 5.1%, p = 0.008; all causes: 38.9% vs. 11.2%, p = 0.002). Seven patients discontinued tofacitinib because of uncontrolled RA activity, and rifampin had been administered concomitantly in four of these seven patients. Of the four patients, three stopped taking tofacitinib in the middle of LTBI treatment, and the DAS28-ESR scores of these patients were higher at discontinuation than at baseline.Conclusion:Discontinuation rates were higher in RA patients who started tofacitinib during chemoprophylaxis involving rifampin than in those who did not receive rifampin. Physicians should be aware that the efficacy of tofacitinib could be decreased by the chemoprophylactic regimen for tuberculosis.Disclosure of Interests:None declared

Adrenal insufficiency, be aware of drug interactions!

Summary A 42-year-old man with complaints of muscle soreness and an increased pigmentation of the skin was referred because of a suspicion of adrenal insufficiency. His adrenocorticotropic hormone and cortisol levels indicated a primary adrenal insufficiency (PAI) and treatment with hydrocortisone and fludrocortisone was initiated. An etiological workup, including an assessment for anti-adrenal antibodies, very long-chain fatty acids, 17-OH progesterone levels and catecholamine secretion, showed no abnormalities. 18Fluorodeoxyglucose positron emission tomography/CT showed bilateral enlargement of the adrenal glands and bilateral presence of an adrenal nodule, with 18fluorodeoxyglucose accumulation. A positive tuberculin test and positive family history of tuberculosis were found, and tuberculostatic drugs were initiated. During the treatment with the tuberculostatic drugs the patient again developed complaints of adrenal insufficiency, due to insufficient dosage of hydrocortisone because of increased metabolism of hydrocortisone. Learning points: Shrinkage of the adrenal nodules following tuberculostatic treatment supports adrenal tuberculosis being the common aetiology. The tuberculostatic drug rifampicin is a CYP3A4 inducer, increasing the metabolism of hydrocortisone. Increase the hydrocortisone dosage upon initiation of rifampicin in case of (adrenal) tuberculosis. A notification on the Addison’s emergency pass could be considered to heighten physician’s and patients awareness of hydrocortisone drug interactions.