Strong CYP2D6 Inhibitors Research Articles

The use of psychotropic drugs in oncological diseases (review)

Background: It is estimated that at least 25-30% of cancer patients experience mental disorders. Due to the high prevalence of these disorders among this patient population, psychotropic drugs have been successfully utilized in oncology for an extended period of time. The use of psychotropic drugs enables targeted symptom management to improve the quality of life of cancer patients. However, it is essential to carefully evaluate the risks of drug interactions and potential side effects when prescribing any psychotropic medication. The aim of the study: The aim of this study was to analyze the utilization of psychopharmacotherapy in oncology practice for treating comorbid mental disorders and symptoms related to oncological diseases. An evaluation of the side effects and drug interactions of psychopharmacological and oncological drugs was conducted. Materials and methods: The eLibrary, PubMed, and Google Scholar databases were searched using the keywords “psychooncology” and “psychopharmacotherapy”. Reviews, meta-analyses, and therapy recommendations were selected from the obtained results, which provided the most comprehensive coverage of the current scientific data on this topic. Results: Anxiety disorders and depressive reactions are prevalent in cancer patients and can be successfully treated with psychopharmacological intervention. Additionally, symptoms associated with the oncological process or side effects of treatment such as anorexia, pain, and nausea can be alleviated through the use of antidepressants and antipsychotics. However, it is crucial to carefully evaluate the risks of drug interactions when prescribing any psychotropic drugs. For instance, strong cytochrome CYP2D6 inhibitors can lead to a decrease in the concentration of the active metabolite tamoxifen, while the combination of antidepressants and tramadol increases the risk of serotonin syndrome. Conclusion: The application of psychotropic drugs in the treatment of cancer can greatly enhance the patients' quality of life. However, potential side effects and drug interactions must be carefully evaluated.

Abstract CT196: First-in-human phase 1/2a trial of a macrocyclic ATR inhibitor (ATRN-119) in patients with advanced solid tumors

Abstract Background: ATRN-119 is an orally bioavailable, potent, selective macrocyclic small molecule inhibitor of Ataxia Telangiectasia and Rad3- related (ATR) kinase. As the master regulator of DNA damage response (DDR), ATR orchestrates cellular response to DNA replication stress to preserve DNA replication fork integrity. Cancer cells with markedly increased oncogenic stress or dysfunctional DDR are more reliant on ATR for genome stabilization. Thus, inhibition of ATR can result in cancer cell-selective replication fork collapse and cancer cell death. Methods: This ongoing, first-in-human, multi-site phase 1/2a trial (NCT04905914) is investigating ATRN-119 safety and pharmacokinetic properties (primary objectives), preliminary efficacy in various solid tumors (secondary objective), and biomarker profile (exploratory objective). This study uses an open-label, standard 3+3 dose escalation and dose expansion study design. Key inclusion criteria include: advanced solid tumor, measurable disease (RECIST v1.1), tumor with at least 1 DDR mutation by next-generation-sequencing, at least 1 failed standard-of-care therapy, ECOG PS 0 or 1, and adequate organ function. Key exclusion criteria are cancer therapy within 4 weeks or at least 5 half-lives, unresolved therapy-related AEs, investigational agent within 5 half-lives or 30 days of study drug, CNS metastases or unstable involvement, and concomitant treatment with strong CYP3A4 or CYP2D6 inhibitors or inducers. Results: This trial is currently enrolling at Dose level 5 (550 mg). Among 12 patients in the first four dose levels, the median age is 62 years (range: 48 to 79), where 67% (n=8) are female, 75% (n=9) are White, and 25% (n=3) are Black. The median number of prior treatments is 3 (range: 1 to 6, and 92% have received platinum-based chemotherapy). The majority of tumors, 75% (n=9), had a TP53 mutation. There have been no reports of dose-limiting toxicities, treatment-related serious adverse events (AE), and treatment-related AEs Grade 3 or higher in these cohorts. The three most commonly reported all-cause AEs are fatigue (33%, n=4), nausea (25%, n=3), and diarrhea (25%, n=3). Increasing exposure and maximum serum concentrations (Cmax) were observed by dose level. The half-life of ATRN-119 is ~5 hours. Two of 12 patients achieved stable disease (SD): one patient from Dose level 1 (50 mg) who progressed on Day 112 and one patient from Dose level 3 (200 mg) who remains on treatment as of Day 118 (data cut off date: January 2, 2024). Conclusion: In these early cohorts, once-daily oral ATRN-119 appears to be well tolerated with a manageable safety profile, exhibits near dose proportionality, and demonstrates disease stabilization warranting further investigation. Further studies to explore a twice-daily schedule are being considered. Citation Format: Fiona Simpkins, Amit Mahipal, Patricia LoRusso, Reva Schneider, Crystal Miller, David Stenehjem, Eric J. Brown, Mike Carleton, Joachim Gullbo, Nadeem Q. Mirza. First-in-human phase 1/2a trial of a macrocyclic ATR inhibitor (ATRN-119) in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT196.

Clinical significance of coadministration of moderate to strong CYP enzyme inhibitors with doxorubicin in breast cancer patients receiving AC chemotherapy.

Cytochrome P450 (CYP) enzyme inhibitors may increase the toxicity of many chemotherapies. Medication databases classify doxorubicin coadministration with CYP2D6 or CYP3A4 inhibitors as either a major interaction or contraindication. This study assessed the incidence of toxicity secondary to doxorubicin given with or without CYP enzyme inhibitors in breast cancer patients receiving doxorubicin and cyclophosphamide. This retrospective study included female breast cancer patients treated with doxorubicin and cyclophosphamide (AC). Patients were divided into three arms: no moderate or strong CYP inhibitor interactions, moderate or strong CYP2D6 inhibitor interactions, or moderate or strong CYP3A4 inhibitor interactions. Primary outcomes included incidence of doxorubicin-associated toxicity, unplanned medical visits, chemotherapy treatment delays, and doxorubicin dose reductions. The secondary endpoint was time to toxicity. There were 171 patients included (n = 20 patients in the CYP2D6 inhibitor group and n = 15 in the CYP3A4 inhibitor group). Neither CYP inhibitor group showed a difference in incidence of hepatotoxicity, cardiotoxicity, myelotoxicity, moderate/severe nausea, or treatment delays. Compared to the no CYP inhibitor group, the CYP2D6 inhibitor group experienced a higher incidence of unplanned medical visits (45% vs. 19.4%; p = 0.023) and more frequent doxorubicin dose reductions (30% vs. 7.2%; p = 0.006). The CYP3A4 inhibitor group did not differ from the no CYP inhibitor group for these outcomes. CYP inhibitors, particularly CYP2D6 inhibitors, may affect doxorubicin tolerability, as seen in this study by an increased incidence of unplanned medical visits and doxorubicin dose reductions.

A Phase I, Open-Label, Fixed Sequence Study to Investigate the Effect of Cytochrome P450 2D6 Inhibition on the Pharmacokinetics of Ulotaront in Healthy Subjects.

Ulotaront is a novel psychotropic agent with agonist activity at trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT1A) receptors in phase III clinical development for the treatment of schizophrenia. This study aimed to investigate the effect of paroxetine, a strong cytochrome P450 (CYP) 2D6 inhibitor, on ulotaront pharmacokinetics (PK) in healthy volunteers. Subjects received a single oral dose of 25 mg ulotaront on Day 1 and an oral dose of 20 mg paroxetine once daily from Days 5 to 10 to achieve steady-state plasma paroxetine levels. On Day 11, subjects received another single oral dose of 25 mg ulotaront, with continued daily oral dosing of 20 mg paroxetine from Days 11 to 14. All 24 subjects were CYP2D6 normal metabolizers. Coadministration of paroxetine increased ulotaront maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to infinity (AUC∞) by 31% and 72%, respectively, and decreased ulotaront apparent clearance (CL/F) by approximately 42%. While coadministration of paroxetine increased AUC∞ of active but minor metabolite SEP-363854 by 32%, it had no effect on SEP-363854 Cmax, or on SEP-363854 to the ulotaront AUC from time zero to the last quantifiable concentration (AUClast) ratio. Based on the acceptable adverse event profile of ulotaront across previous phase II studies, the increase in ulotaront exposure is unlikely to be clinically meaningful. Weak drug-drug interactions were observed between ulotaront and the strong CYP2D6 inhibitor paroxetine; however, dose adjustment as a precondition when ulotaront is coadministered with strong CYP2D6 inhibitors or administered to CYP2D6 poor metabolizers should not be necessary.

A clinical pharmacokinetic drug-drug interaction study between dextromethorphan and emvododstat, a potent anti-SARS-CoV-2 dihydroorotate dehydrogenase inhibitor

PurposeA therapeutic agent that targets both viral replication and the hyper-reactive immune response would offer a highly desirable treatment for severe acute respiratory syndrome corona virus 2 (SARS-CoV-2, coronavirus disease 2019, COVID-19) management. Emvododstat (PTC299; 4-chlorophenyl 6-chloro-1-[4-methoxyphenyl]-1,3, 4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate) was found to be a potent inhibitor of immunomodulatory and inflammation-related processes by inhibition of dihydroorotate dehydrogenase to reduce the severity of SARS-CoV-2 infections This drug interaction study was performed to determine if emvododstat was an inhibitor of CYP2D6.MethodsPotential drug-drug interactions between emvododstat and a CYP2D6 probe substrate (dextromethorphan) were investigated by measuring plasma dextromethorphan and metabolite (dextrorphan) concentrations before and after emvododstat administration. On day 1, 18 healthy subjects received an oral dose of 30 mg dextromethorphan followed by a 4-day washout period. On day 5, subjects received an oral dose of 250 mg emvododstat with food. Two hours later, 30 mg dextromethorphan was administered.ResultsWhen given with emvododstat, plasma dextromethorphan concentrations increased substantially, while metabolite levels (dextrorphan) remained essentially the same. Maximum plasma dextromethorphan concentration (Cmax) increased from 2006 to 5847 pg/mL. Dextromethorphan exposure (AUC) increased from 18,829 to 157,400 h·pg/mL for AUC0-last and from 21,585 to 362,107 h·pg/mL for AUC0-inf following administration of emvododstat. When dextromethorphan parameters were compared before and after emvododstat, least squares mean ratios (90% confidence interval) were found to be 2.9 (2.2, 3.8), 8.4 (6.1, 11.5), and 14.9 (10.0, 22.1) for Cmax, AUC0-last, and AUC0-inf, respectively.ConclusionEmvododstat appears to be a strong CYP2D6 inhibitor. No drug-related treatment emergent adverse effects (TEAEs) were considered to be severe or serious.Trial registrationEudraCT 2021-004626-29, 11 May 2021.

Females present higher dose-adjusted drug concentrations of metoprolol and allopurinol/oxypurinol than males.

Females present a higher risk of adverse drug reactions. Sex-related differences in drug concentrations may contribute to these observations but they remain understudied given the underrepresentation of females in clinical trials. The aim of this study was to investigate whether anthropometric and socioeconomic factors and comorbidities could explain sex-related differences in concentrations and dosing for metoprolol and oxypurinol, the active metabolite of allopurinol. We conducted an analysis of two cross-sectional studies. Participants were self-described "White" adults taking metoprolol or allopurinol selected from the Montreal Heart Institute Hospital Cohort. A total of 1007 participants were included in the metoprolol subpopulation and 459 participants in the allopurinol subpopulation; 73% and 86% of the participants from the metoprolol and allopurinol subpopulations were males, respectively. Females presented higher age- and dose-adjusted concentrations of both metoprolol and oxypurinol (both p<0.03). Accordingly, females presented higher unadjusted and age-adjusted concentration:dose ratio of both metoprolol and allopurinol/oxypurinol compared to males (all p<3.0 × 10-4 ). Sex remained an independent predictor of metoprolol concentrations (p < 0.01), but not of oxypurinol concentrations, after adjusting for other predictors. In addition to sex, age, daily dose, use of moderate to strong CYP2D6 inhibitors, weight, and CYP2D6 genotype-inferred phenotype were associated with concentrations of metoprolol (all p < 0.01). Daily dose, weight, estimated glomerular filtration rate (eGFR), and employment status were associated with oxypurinol concentrations (all p < 0.01). Females present higher dose-adjusted concentrations of metoprolol and oxypurinol than males. This suggests the need for sex-specific dosing requirements for these drugs, although this hypothesis should be validated in prospective studies.

Pharmacogenetic CYP2D6 variability, phenoconversion and treatment outcomes: A Danish population-based cohort study in 6,798 individuals initiating atomoxetine treatment

IntroductionAtomoxetine, a first-line treatment option for ADHD, is affected by pharmacogenetic (PGx) variation of the drug-metabolizing enzyme CYP2D6. Despite the recommendation of CYP2D6 testing, the use of PGx-guided dosing remains low in Denmark.ObjectivesWe investigated wide-ranging clinical outcomes in atomoxetine users in association with PGx variability.MethodsWe analyzed 6,798 individuals (55% children) with a first prescription for atomoxetine identified from the Danish population-based iPSYCH case-cohort study linking biobank information with Danish registers. Individuals were categorized based on their single-nucleotide-polymorphism-based CYP2D6 genotype into normal (NM), intermediate (IM), and poor metabolizer (PM). Clinical outcomes included treatment switching, discontinuation, psychiatric inpatient-, outpatient-, and emergency contact, suicide attempt/self-harm, sleep problem, and depression. Individuals’ CYP2D6-status could change due to drug-drug-interactions of weak, intermediate, or strong-CYP2D6 inhibitors (phenoconversion), which we accounted for by time-varying phenotype assessment. Incidence rate ratios (IRR) were estimated using Poisson regression analyses and adjusted for a wide range of potential confounders and covariates.ResultsOver two-thirds of the individuals had a hospital diagnosis of ADHD at the first atomoxetine prescription. The distribution of CYP2D6 phenotypes was similar in children and adults. IM/PM children had a significantly higher risk of a sleeping problem compared with NM children (IRR 1.25, 95% CI 1.01-1.54). Compared with NM adults, those with IM/PM had a higher risk of switching (1.15, 95% CI 0.98-1.35).ConclusionsThis is the first study showing the potential impact of PGx variability on clinical outcomes of atomoxetine users in a population-based setting, highlighting the utility of PGx testing.DisclosureNo significant relationships.

Population pharmacokinetics of rucaparib in patients with advanced ovarian cancer or other solid tumors.

To develop a population pharmacokinetics (PPK) model for rucaparib, an oral poly(ADP-ribose) polymerase inhibitor. The PPK analysis used PK data from patients in Study 1014 (NCT01009190, n = 35), Study 10 (NCT01482715, n = 123), and ARIEL2 (NCT01891344, n = 300), including intensive intravenous data (12-40mg), intensive and sparse oral data (12-360mg single-dose, 40-500mg once daily, and 240-840mg twice daily [BID]), and intensive single-dose oral data under fasted conditions and after a high-fat meal (40, 300, and 600mg). Rucaparib PK was well described by a two-compartment model with sequential zero-order release and first-order absorption and first-order elimination. A high-fat meal slightly increased bioavailability at 600mg but not at lower doses; this is not considered clinically significant, and rucaparib can be taken with or without food. Covariate effects of baseline creatinine clearance and albumin on rucaparib clearance were identified. Despite numerical increases in exposure with renal impairment, no dose adjustment is recommended for patients with mild or moderate renal impairment. No statistically significant relationships were detected for demographics, hepatic function (normal versus mild impairment), CYP1A2 and CYP2D6 phenotypes, or strong CYP1A2 or CYP2D6 inhibitors. Concomitant proton pump inhibitors showed no clinically significant effect on absorption. External validation of the model with data from ARIEL3 (NCT01968213) and TRITON2 (NCT02952534) studies showed no clinically meaningful PK differences across indications or sex. The PPK model adequately described rucaparib PK, and none of the covariates evaluated had a clinically relevant effect. GOV: Study 1014 (NCT01009190), Study 10 (NCT01482715), ARIEL2 (NCT01891344), ARIEL3 (NCT01968213), and TRITON2 (NCT02952534).

Population Pharmacokinetic Modeling and Exposure-Response Analysis for Aripiprazole Once Monthly in Subjects With Schizophrenia.

An intramuscular formulation of aripiprazole monohydrate dosed once monthly (AOM) was developed to address nonadherence with the approved oral tablets. A 3-compartment linear population pharmacokinetic model for oral and AOM doses was developed; relative bioavailability was estimated for AOM relative to oral dosing and body mass index and sex were significant predictors of AOM absorption rate constant (longer absorption half-life for women and absorption half-life increases with increasing body mass index). Aripiprazole apparent oral clearance for subjects with cytochrome P450 (CYP) 2D6 poor metabolizer status and in the presence of strong CYP2D6 inhibitors was approximately half that of subjects with CYP2D6 extensive metabolizer status and 24% lower in the presence of strong CYP3A4 inhibitors. Simulations of the population pharmacokinetics were conducted to evaluate the effect of different dose initiation strategies for AOM, the effects of CYP2D6 metabolizer status, coadministration of CYP2D6 and CYP3A4 inhibitors, and missed doses. An exposure-response model with an exponential hazard function of the model-predicted minimum concentration (Cmin ) described the time to relapse. The hazard ratio (95% confidence interval) was 4.41(2.89-6.75). Thus, a subject with a diagnosis of schizophrenia and Cmin ≥95ng/mL is 4.41 times less likely to relapse relative to a subject with Cmin <95ng/mL.

Application of Physiologically Based Pharmacokinetic Modeling to Evaluate the Drug-Drug and Drug-Disease Interactions of Apatinib.

Aim: Apatinib is an orally administered vascular epidermal growth factor receptor (VEGFR)-tyrosine kinase inhibitors approved for the treatment of advanced gastric adenocarcinoma or gastric esophageal junction adenocarcinoma. Apatinib is predominantly metabolized by CYP3A4/5, followed by CYP2D6. The present study aimed to evaluate the potential drug–drug interaction (DDI) and drug–disease interaction (DDZI) risks of apatinib in Chinese volunteers. Methods: Modeling and simulation were conducted using Simcyp Simulator. The input parameters required for modeling were obtained from literature research or experiments. Then, the developed physiologically based pharmacokinetic (PBPK) models were applied to evaluate single-dose DDI potential in Chinese healthy volunteers with weak and moderate CYP3A inhibitors, strong CYP2D6 inhibitors, as well as CYP3A4 inducers. The DDZI potential was also predicted in patients with hepatic or renal impairment. Results: The developed PBPK models accurately assessed apatinib pharmacokinetics following single-dose administration in Chinese healthy volunteers and cancer patients. The DDI simulation showed 2–4-fold changes in apatinib exposures by moderate CYP3A4 inhibitors and CYP3A4 inducers. A moderate increase of apatinib exposure (1.25–2-fold) was found with strong CYP2D6 inhibitor. In the DDZI simulation with hepatic impairment, the AUC of apatinib was significantly increased by 2.25-fold and 3.04-fold for Child–Pugh B and Child–Pugh C, respectively, with slightly decreased Cmax by 1.54 and 1.67-fold, respectively. Conclusion: The PBPK models developed in the present study would be highly beneficial to quantitatively predict the pharmacokinetic changes of apatinib under different circumstances, which might be difficult to evaluate clinically, so as to avoid some risks in advance.

A Population Pharmacokinetic Meta-Analysis of Veliparib, a PARP Inhibitor, Across Phase 1/2/3 Trials in Cancer Patients.

Veliparib (ABT‐888) is a poly(ADP‐ribose) polymerase inhibitor in development for the treatment of high‐grade ovarian cancer or BRCA‐mutated breast cancer in combination with carboplatin and paclitaxel. The population pharmacokinetics of veliparib were characterized using combined data from 1470 adult subjects with ovarian cancer, breast cancer, or other solid tumors enrolled in 6 phase 1 studies, 1 phase 2 study, and 2 phase 3 studies of veliparib oral doses of 10 to 400 mg twice daily as monotherapy or in combination with chemotherapy. A 1‐compartment model with linear clearance and first‐order absorption best characterized veliparib pharmacokinetics. The predicted apparent oral clearance (CL/F) and volume of distribution (Vc/F) were 479 L/day and 152 L, respectively. The significant covariates in the final model included albumin, creatinine clearance, strong inhibitors of cytochrome P450 (CYP) 2D6, and sex on CL/F and albumin, body weight, and sex on Vc/F. Mild and moderate renal impairment increased veliparib median (95%CI) steady‐state AUC (AUCss) by 27.3% (23.7%‐30.9%) and 65.4% (56.0%‐75.5%), respectively, compared with normal renal function. Male subjects had 16.5% (7.53%‐23.9%) lower AUCss compared with female subjects and coadministration with strong CYP2D6 inhibitors increased AUCss by 13.0% (6.11%‐20.8%). Race, age, region, cancer type, or enzyme (CYP3A4, CYP2C19) or transporter (P‐glycoprotein, multidrug and toxin extrusion protein 1/2, organic cation transporter 2) inhibiting/inducing comedications were not found to significantly impact veliparib pharmacokinetics. Other than baseline creatinine clearance and hence renal impairment effect on veliparib clearance, no other covariates had a clinically meaningful effect on veliparib exposure warranting dose adjustment.

Impact of Paroxetine, a Strong CYP2D6 Inhibitor, on SPN-812 (Viloxazine Extended-Release) Pharmacokinetics in Healthy Adults.

SPN‐812 (viloxazine extended‐release) is a novel nonstimulant recently approved as a treatment for attention‐deficit/hyperactivity disorder in children and adolescents. Given that SPN‐812 is metabolized by CYP2D6 and may be coadministered with CYP2D6 inhibitors, this trial investigated the pharmacokinetics and safety of SPN‐812 coadministered with the potent CYP2D6 inhibitor paroxetine. In this single‐sequence, 3‐treatment period study in healthy volunteers, subjects received a single oral dose of 700 mg SPN‐812 alone (period 1), 20 mg daily paroxetine (10 days, period 2), followed by concurrent administration of SPN‐812 and paroxetine (period 3). Blood samples were collected for 72 hours post‐SPN‐812 dosing and analyzed for viloxazine and its primary metabolite, 5‐HVLX‐gluc. Twenty‐two healthy adults were enrolled; all completed the trial. The potential for drug interaction between SPN‐812 and paroxetine was assessed using analysis of variance on the log‐transformed pharmacokinetic parameters Cmax, AUC0‐t, and AUCinf. The least‐squares geometric mean ratios for viloxazine were (reported as the ratio of combination/SPN‐812 alone) Cmax, 116.04%; 90%CI, 109.49%‐122.99%; AUC0‐t, 134.65%; 90%CI, 127.65‐142.03; and AUCinf, 134.80%; 90%CI, 127.94%‐142.03%. CYP2D6 inhibition resulted in a modest change (<35%) on viloxazine AUCs with no change in Cmax. All adverse events were mild in severity.

Effects of paroxetine, ketoconazole, and rifampin on the metabolism of eliglustat, an oral substrate reduction therapy for Gaucher disease type 1

Eliglustat is an oral glucosylceramide synthase inhibitor indicated for the long-term treatment of adults with Gaucher disease type 1 and CYP2D6 extensive, intermediate, or poor metabolizer phenotypes. Eliglustat is metabolized primarily by CYP2D6 and to a lesser extent by CYP3A4 and is a substrate of P-glycoprotein (P-gp). Three studies evaluated the effects of paroxetine (strong CYP2D6 inhibitor), ketoconazole (strong CYP3A4 and P-gp inhibitor), and rifampin (strong CYP3A4/P-gp inducer; OATP inhibitor) on the pharmacokinetics of orally administered eliglustat in healthy adults. An 8.9-fold increase in eliglustat exposure following co-administration of multiple-dose eliglustat and paroxetine is attributed to inhibition of CYP2D6-mediated metabolism of eliglustat by paroxetine. A 4.3-fold increase in eliglustat exposure following co-administration of multiple-dose eliglustat and ketoconazole is attributed to inhibition of CYP3A4-mediated metabolism and/or P-gp-mediated transport of eliglustat by ketoconazole. Co-administration of eliglustat with oral doses of rifampin reduced eliglustat exposure by >85% due to induction of CYP3A4/P-gp by rifampin, while a single intravenous dose of rifampin had no effect on eliglustat, confirming that eliglustat is not an OATP substrate. Depending on CYP2D6 metabolizer phenotype, co-administration of eliglustat with CYP2D6 and/or CYP3A inhibitors or CYP3A inducers may alter eliglustat exposure, warrant dosage adjustment or use with caution, or be contraindicated.

First noncontrolled substance approved to treat narcolepsy in adults

In August, FDA approved pitolisant (Wakix—Harmony Biosciences) for treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy. The selective histamine-3 receptor antagonist/inverse agonist is the first and only treatment for narcolepsy that is not scheduled as a controlled substance. “The approval of Wakix provides health care professionals managing people living with narcolepsy a new and important treatment option for their patients,” said Jeffrey Dayno, MD, Harmony Bioscience’s chief medical officer, in a statement. “Wakix … offers an important benefit/risk profile to address the unmet medical need that exists in people living with narcolepsy.” Pitolisant is available as both a 4.45-mg and 17.8-mg tablet and should be stored at 20°C to 25°C (68°F to 77°F). FDA’s approval was based on Harmony 1 and Harmony 1bis—two multicenter, double-blind, placebo-controlled studies. The studies randomized 261 patients to receive pitolisant, placebo, or active control. Participants were treated for 8 weeks, including a 3-week dose-titration phase followed by a 5-week stable-dose phase. In both studies, patients treated with pitolisant showed statistically significant improvement in EDS, as measured by the Epworth Sleepiness Scale. Common adverse effects of pitolisant include insomnia, nausea, and anxiety. The drug may also cause QT interval prolongation. Pitolisant may interact with a number of drugs. Its use with strong CYP2D6 inhibitors, for instance, increases the amount of pitolisant that patients are exposed to by 2.2-fold. The dose of pitolisant should be reduced by one-half, with a maximum dosage of 17.8 mg once daily, for patients who are concurrently using strong CYP2D6 inhibitors. Use of pitolisant with strong CYP3A4 inducers decreases the amount of pitolisant exposure in the blood by 50%. In patients taking CYP3A4 inducers, a dose adjustment should be considered, as detailed in pitolisant’s prescribing information. Pitolisant works by increasing the synthesis and release of histamine, so use of the drug with histamine-1 (H1) receptor antagonists that cross the blood–brain barrier may reduce its effectiveness. Patients taking pitolisant should avoid using centrally acting H1 receptor antagonists. Because pitolisant can prolong the QT interval, the drug should not be used in combination with other drugs that cause QT prolongation, as this can increase the risk of cardiac arrhythmia. Pitolisant may also reduce the effectiveness of sensitive CYP3A4 substrates, including hormonal contraceptives. Before they begin treatment with pitolisant, advise patients to inform their physician if they are taking, or planning to take, any prescription or OTC drugs. Counsel patients to consult their physician immediately if they feel faint, lose consciousness, or have heart palpitations, as these could be signs of prolongation of the QT interval. Pitolisant (Wakix)Manufacturer: Harmony BiosciencesDrug class: Histamine-3 (H3) receptor antagonist/inverse agonistIndication: Treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsyDosage: 17.8 mg to 35.6 mg once daily, taken orally in the morning upon awakening. Week 1: Start with 8.9 mg. Week 2: Increase dosage to 17.8 mg. Week 3: May increase to the maximum-recommended dosage of 35.6 mg. See prescribing information for more details.Of note: Pitolisant is contraindicated in patients with severe hepatic impairment (Child-Pugh C). The drug may increase the QT interval and could reduce the efficacy of hormonal contraceptives. Manufacturer: Harmony Biosciences Drug class: Histamine-3 (H3) receptor antagonist/inverse agonist Indication: Treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy Dosage: 17.8 mg to 35.6 mg once daily, taken orally in the morning upon awakening. Week 1: Start with 8.9 mg. Week 2: Increase dosage to 17.8 mg. Week 3: May increase to the maximum-recommended dosage of 35.6 mg. See prescribing information for more details. Of note: Pitolisant is contraindicated in patients with severe hepatic impairment (Child-Pugh C). The drug may increase the QT interval and could reduce the efficacy of hormonal contraceptives. Pitolisant is metabolized extensively by the liver and is contraindicated in patients with severe hepatic impairment because the drug has not been studied in this population. Health care providers should monitor patients with moderate hepatic impairment, as these patients have shown increased amounts of the drug in their blood. Patients with mild hepatic impairment who are taking pitolisant should also be closely monitored. Emphasize to patients of reproductive potential that pitolisant may reduce the efficacy of hormonal contraceptives. Counsel these patients to use an alternative nonhormonal contraceptive method during treatment with pitolisant and for at least 21 days after discontinuing treatment. If a patient becomes pregnant during treatment with pitolisant, inform them that a pregnancy exposure registry is available to monitor pregnancy outcomes of the drug; patients can call 1-800-833-7460 to enroll or obtain information.

Efficacy of Tramadol for Pain Management in Patients Receiving Strong Cytochrome P450 2D6 Inhibitors.

Tramadol is metabolized by cytochrome P450 (CYP) 2D6 to form an active metabolite that exhibits its analgesic effect. Medications that inhibit this enzyme are used often in practice, yet the clinical impact of this interaction on the analgesic effects of tramadol has yet to be fully described. The objective was to determine whether a clinically relevant decrease in pain control is observed in patients taking scheduled tramadol concomitantly with a strong CYP2D6 inhibitor. Retrospective cohort study. Large health care system. One hundred fifty-two adult inpatients who received scheduled tramadol for at least 24hours with (76 patients) or without (76 patients) a strong CYP2D6 inhibitor between January 1, 2012, and February 28, 2017, were included in the analysis. Patients hospitalized for opioid use disorder or those receiving substandard dosing of tramadol were excluded. The primary outcome was mean breakthrough opiate consumption in the presence and absence of CYP2D6 inhibitors. Secondary outcomes included mean pain scores, length of hospital stay, tramadol discontinuation rates, and prespecified subgroup analyses based on patient sex, race, and specific CYP2D6 inhibitor administered. Patients receiving concurrent CYP2D6 inhibitors required significantly more breakthrough morphine milligram equivalents per day compared with patients receiving scheduled tramadol without CYP2D6 inhibitors (geometric mean±SD 18.2±6.3 vs 5.7±6.7mg morphine milligram equivalents, p<0.001). No significant differences existed between cohorts for mean pain score, length of hospital stay, or tramadol discontinuation rate. This study demonstrated a clinically relevant decrease in the efficacy of tramadol when used for pain control in patients receiving a strong CYP2D6 inhibitor. These results should encourage clinicians to review medication lists for this interaction and adjust regimens accordingly to ensure adequate pain control.

Top New Drug Approvals of 2018

Top New Drug Approvals of 2018

Discontinuation and dose adjustment of metoprolol after metoprolol-paroxetine/fluoxetine co-prescription in Dutch elderly.

PurposeCo‐prescription of paroxetine/fluoxetine (a strong CYP2D6 inhibitor) in metoprolol (a CYP2D6 substrate) users is common, but data on the clinical consequences of this drug‐drug interaction are limited and inconclusive. Therefore, we assessed the effect of paroxetine/fluoxetine initiation on the existing treatment with metoprolol on the discontinuation and dose adjustment of metoprolol among elderly.MethodsWe performed a cohort study using the University of Groningen IADB.nl prescription database (www.IADB.nl). We selected all elderly (≥60 years) who had ever been prescribed metoprolol and had a first co‐prescription of paroxetine/fluoxetine, citalopram (weak CYP2D6 inhibitor), or mirtazapine (negative control) from 1994 to 2015. The exposure group was metoprolol and paroxetine/fluoxetine co‐prescription, and the other groups acted as controls. The outcomes were early discontinuation and dose adjustment of metoprolol. Logistic regression was applied to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI).ResultsCombinations of metoprolol‐paroxetine/fluoxetine, metoprolol‐citalopram, and metoprolol‐mirtazapine were started in 528, 673, and 625 patients, respectively. Compared with metoprolol‐citalopram, metoprolol‐paroxetine/fluoxetine was not significantly associated with the early discontinuation and dose adjustment of metoprolol (OR = 1.07, 95% CI:0.77‐1.48; OR = 0.87, 95% CI:0.57‐1.33, respectively). In comparison with metoprolol‐mirtazapine, metoprolol‐paroxetine/fluoxetine was associated with a significant 43% relative increase in early discontinuation of metoprolol (OR = 1.43, 95% CI:1.01‐2.02) but no difference in the risk of dose adjustment. Stratified analysis by gender showed that women have a significantly high risk of metoprolol early discontinuation (OR = 1.62, 95% CI:1.03‐2.53).ConclusionParoxetine/fluoxetine initiation in metoprolol prescriptions, especially for female older patients, is associated with the risk of early discontinuation of metoprolol.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy.

Tamoxifen is biotransformed by CYP2D6 to 4-hydroxytamoxifen and 4-hydroxy N-desmethyl tamoxifen (endoxifen), both with greater antiestrogenic potency than the parent drug. Patients with certain CYP2D6 genetic polymorphisms and patients who receive strong CYP2D6 inhibitors exhibit lower endoxifen concentrations and a higher risk of disease recurrence in some studies of tamoxifen adjuvant therapy of early breast cancer. We summarize evidence from the literature and provide therapeutic recommendations for tamoxifen based on CYP2D6 genotype.

Assessment of a clinical and genetic algorithm to predict endoxifen concentration.

e12021Background: Tamoxifen ineffectiveness in patients with hormone receptor + breast cancer may be attributed to subtherapeutic concentrations of its active metabolite, endoxifen. Teft et al. previously published an algorithm that integrates clinical and genetic variables to predict endoxifen concentration. The objective of this analysis was to assess the accuracy of this algorithm in two independent cohorts of tamoxifen treated patients. Methods: Two cohorts of patients taking 20 mg tamoxifen daily and not concomitantly receiving strong CYP2D6 inhibitors were enrolled in UNC LCCC 0801. Endoxifen was measured on two different assays, one measured Z- and E-endoxifen (cohort 1, n = 68), the other Z-endoxifen only (cohort 2, n = 293). Actual endoxifen concentration in the validation cohorts was compared with the Teft algorithm prediction using Pearson correlation and parameter estimates from all cohorts were visually compared. Results: Modest correlation was found for cohort 1 (concordance correlation = 0....

Abstract P5-12-06: Comprehensive assessment of the effect of genetic polymorphisms in drug metabolizing enzymes and transporters on tamoxifen activation to endoxifen

Abstract Background: Tamoxifen is the most commonly prescribed hormonal drug for estrogen receptor positive breast cancer treatment. Tamoxifen itself has weak anti-estrogenic activity, but is bioactivated to the more potent inhibitor endoxifen. Recent data suggest inferior efficacy of tamoxifen treatment in patients who have low systemic endoxifen concentration. Genetic variability in drug metabolizing enzymes and transporters, particularly CYP2D6, are known to effect serum endoxifen concentration. The association of CYP2D6 genotype and endoxifen concentration is well established; however, there is a paucity of data regarding the effects of genetic variants in other drug metabolizing enzymes and transporters on endoxifen concentrations. The objective of our study was to comprehensively screen known, functionally consequential polymorphisms and copy number variations in genes of interest to detect additional pharmacogenetic predictors of endoxifen concentration during tamoxifen treatment. Methods: This analysis includes patients prospectively enrolled on the Lineberger Comprehensive Cancer Center 0801 trial. Patients had received tamoxifen for a minimum of 4 months prior to enrollment and were not concurrently taking strong or moderate CYP2D6 inhibitors. Samples were collected at enrollment for measurement of steady state endoxifen level and collection of germline DNA. Genotyping was performed for CYP2D6 using the Amplichip® CYP450 test (Roche Diagnostics) and for other candidate genes (CYP2C9, CYP3A4, CYP3A5, ABCB1, SLCO1B1, SULT1A1, SULT1A2, and UGT2B7) using the iPLEX® ADME PGx Pro Panel (Agena Bioscience). Activity phenotype for each gene was inferred from genotype data based on known activity of variant alleles or copy numbers. Metabolite concentrations were measured via LC/MS-MS assay at Indiana University and square root transformed prior to analysis to improve normality. Linear regression models were used to evaluate the association of each gene individually with endoxifen concentration, assuming an additive pharmacogenetic effect, after adjustment for CYP2D6 phenotype (EM/UM, IM or PM). Results: 304 Patients with steady-state endoxifen concentration and successful genotyping were included in the analysis. After transformation and adjustment, endoxifen concentration was significantly associated with carrying low-activity CYP2C9 variant alleles (*2, *3, *5, *6, *8, *11, *12) (p=0.016). Predicted endoxifen concentration based on CYP2C9 and CYP2D6 genotype can be found in. Predicted endoxifen concentration (ng/mL) based on CYP2C9 and CYP2D6 Phenotype CYP2D6 EM/UMCYP2D6 IMCYP2D6 PMCYP2C9 WT/WT9.716.553.41CYP2C9 WT/Var8.375.482.63CYP2C9 Var/Var7.134.481.96Abbreviations: WT= wild-type, Var=Variant allele for CYP2C9 Phenotype activity of other enzymes and transporters was not associated with endoxifen concentration (all p&amp;gt;0.05). Conclusions: Polymorphisms in CYP2C9 and CYP2D6, but not other enzymes or transporters, contribute to variation in endoxifen exposure. If endoxifen exposure is validated to predict tamoxifen efficacy, personalized tamoxifen dosing algorithms should include CYP2C9, in addition to CYP2D6 and clinical factors, to improve efficacy and minimize side effects. Citation Format: Hertz DL, Danko W, Deal A, Walko CM, Flockhart DA, McLeod HL, Ibrahim JG, Irvin Jr WJ. Comprehensive assessment of the effect of genetic polymorphisms in drug metabolizing enzymes and transporters on tamoxifen activation to endoxifen. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-12-06.