Assessment of Potential Drug-Drug Interactions Among Patients With Ovarian Cancer Receiving Olaparib

<p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d611772e81"> <b>Objectives:</b> Based on data compiled in the publicly-available LactMed database, breastfeeding mothers taking CYP3A inhibitors or inducers (ritonavir, itraconazole, efavirenz, and rifampin) expose their infants to these drugs at subtherapeutic levels. Whether these subtherapeutic exposures can cause significant drug-drug interactions (DDIs) if the infants are administered CYP3A substrates is not known. The aim of this analysis is to evaluate the DDI potential in infants between CYP3A inhibitors or inducers administered through breastmilk and the established CYP3A probe substrate midazolam using a combination of information about medication concentrations from LactMed with physiologically based pharmacokinetic (PBPK) simulations. These results can be extrapolated to other sensitive CYP3A substrates administered to infants. <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d611772e86"> <b>Methods:</b> PBPK modeling was performed using Simcyp V23 to evaluate DDIs in a breastfed infant taking midazolam while the mother is administered CYP3A inducers or inhibitors. The reported concentrations of the CYP3A inducers efavirenz [ <a class="xref-link" href="#r1">1</a>, <a class="xref-link" href="#r2">2</a>] and rifampicin [ <a class="xref-link" href="#r3">3</a>, <a class="xref-link" href="#r4">4</a>] and the CYP3A inhibitors itraconazole [ <a class="xref-link" href="#r5">5</a>, <a class="xref-link" href="#r6">6</a>] and ritonavir [ <a class="xref-link" href="#r7">7</a>, <a class="xref-link" href="#r8">8</a>] in breastmilk were extracted from the LactMed database. The drug concentrations were used to calculate the total dose of these medications administered to the infant in breastmilk consumed daily by an exclusively breastfed 6-month-old infant according to the FDA guidelines [ <a class="xref-link" href="#r9">9</a>], assuming dosing 8 times a day. Using Simcyp’s pediatric population model, a fixed individual trial was designed to specifically simulate 6-month-old infants [ <a class="xref-link" href="#r10">10</a>]. The PBPK simulations for these infants were performed to evaluate the pharmacokinetics of midazolam in the presence and absence of these medications. Results were summarized for changes in the area under the curve (AUC) and maximum concentration (Cmax) of midazolam. <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d611772e122"> <b>Results:</b> The PBPK simulations of the PK for these medications in breast-fed infants were consistent with the values reported in the LactMed database. Additionally, the PBPK simulations demonstrated varying degrees of DDIs between midazolam and maternal medications in a breastfed infant. Changes in midazolam exposure in the infant when the mother was taking CYP3A inducers or inhibitors ranged from having a moderate effect to not having a clinically relevant effect. <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d611772e127"> <b>Conclusions:</b> Overall, the findings suggest that even though breastfed infants are exposed to sub-therapeutic levels of the considered CYP3A inhibitors and inducers, those exposures are sufficient to introduce DDIs if the infants are taking sensitive CYP3A substrates. These results highlight the importance of considering maternal drug use when evaluating pharmacokinetic changes in drugs directly administered to breastfed infants.

Role of CYP3A in Oral Contraceptives Clearance.

e17556 Background: Homologous recombination and DNA repair are important for genome maintenance. Genetic variations in essential homologous recombination genes, including BRCA1 and BRCA2, results in homologous recombination deficiency (HRD) can be a target for therapeutic strategies of ovarian cancer (OC) including poly (ADP-ribose) polymerase inhibitors (PARPi). Here, we proposed an emerging method based on ADx-GSS algorithm to predict HRD status and explore the correlation between HRD status and first-line maintenance therapy of Olaparib in OC patients or Olaparib maintenance therapy in platinum-sensitive relapsed (PSR) OC patients. Methods: Formalin-fixed, paraffin-embedded tissues of 38 consented OC patients between January 2016 and March 2021 were retrospectively collected. Genomic DNA was extracted and subjected to AmoyDx HRD Focus Panel (Amoy Diagnostics Co., Ltd) covering HRD score and BRCA1/2. The HRD score was calculated as the weighted sum of different types of copy number variation (CNV) trained through BRCAness events. Tumors were defined as genomic instability with an HRD score of ≥ 50 (i.e. HRD-positive). The primary endpoint was progression-free survival (PFS), and was assessed by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Results: Histology of collected samples were mostly serous OC (84.2%). All samples were at stage III-IV (80.84%). The fractions of HRD-positive (n = 26) and HRD-negative (n = 12) group were 68.4%, and 31.6%, respectively. 65.8% (n = 25) of the OC patients had received Olaparib first-line maintenance therapy and 34.2% (n = 13) of PSR patients had received Olaparib maintenance therapy. In December 2021, 34.2% (n = 13) of the whole patients had relapsed. A significant PFS benefit was seen in HRD-positive patients compared with HRD-negative ones (P = 0.0017) or in the first-line maintenance treated population (P = 0.0068). In patients with HRD-positive tumors that did not have BRCA mutations, the PFS benefit was improved versus HRD-negative patients without BRCA mutations. However, Olaparib showed no efficacy difference between HRD-positive and HRD-negative tumor in PSR OC patients. Conclusions: HRD status tested by AmoyDx HRD Focus Panel is significantly correlated with the efficacy of Olaparib, and our results demonstrated a significant PFS benefit for HRD-positive patients compared with HRD-negative patients, especially for patients received Olaparib first-line maintenance therapy.

Despite its success antiretroviral therapy (ART) is still associated with a significant risk of toxicity and subsequent virological failure. Pending the introduction of drugs with greater potency and durability one of the most pressing priorities in HIV treatment is to identify ways in which to maximize the efficacy of existing therapeutic options while minimizing its toxicity. Resistance testing has been shown to be one such strategy. Therapeutic drug monitoring (TDM) for HIV drugs has been widely proposed as another tool by which treatment may be optimized. There are some parallels with resistance testing not least the potential difficulties or pitfalls in interpreting test results and the understandable pressure for provision of this service in the face of increasingly limited treatment options notwithstanding the current lack of data from controlled clinical studies. In this reviews we shall discuss the value of TDM in the context of a ‘monitoring service (in other words drug concentrations are provided in conjunction with interpretation and advice) rather than a facility for ‘measuring drug concentrations. This distinction is important since the interpretation of drug concentrations is fraught with complexity. (excerpt)

IntroductionValbenazine and deutetrabenazine (vesicular monoamine transporter 2 inhibitors) are approved for tardive dyskinesia (TD) treatment in adults. To prevent potential drug-drug interactions (DDIs), valbenazine labeling recommends doses 40 mg/day when taking strong CYP3A4 or CYP2D6 inhibitors and avoidance of strong CYP3A4 inducers and monoamine oxidase inhibitors (MAOIs). Deutetrabenazine labeling recommends doses ≤36-mg/day when taking strong CYP2D6 inhibitors and avoidance of MAOIs. This study estimated proportions of patients with TD at risk of DDIs with valbenazine/deutetrabenazine in real-world practice.MethodsPatients aged ≥18 years with TD and ≥1 antipsychotic claim(s) and no valbenazine/ deutetrabenazine claims ≥3 months prior and ≥12 months after diagnosis were identified in the Symphony Health Sciences database (US-based medical, hospital, and pharmacy claims database). Proportions of patients meeting valbenazine/deutetrabenazine concomitant medication labeling restrictions were summarized descriptively.Results14,264/66,046 patients with TD met inclusion criteria. Proportions of patients at potential risk of DDIs were lower with deutetrabenazine ≤36 mg/day (0.2%) and &gt;36 mg/day (21%) versus valbenazine 40 mg/day (4.4%; 22-times difference) and &gt;40 mg/day (28%; 1.3-times difference). Across age groups, underlying conditions (major depressive, mood, and bipolar disorders; schizophrenia), and payer types, proportions of patients at potential risk of DDIs were lower with deutetrabenazine ≤36 mg/day (0.0%– 0.5%) and &gt;36 mg/day (14%– 30%) versus valbenazine 40 mg/day (3%– 5%; 8.0- to &gt;40.0times difference) and &gt;40 mg/day (22%– 35%; 1.2- to &gt;1.5-times difference).ConclusionsEstimated proportions of patients with TD at potential risk of DDIs was lower with deutetrabenazine versus valbenazine overall and across age, underlying conditions, and payer types.FundingTeva Branded Pharmaceutical Products R&amp;D, Inc.

Introduction: Incidence of stroke is more frequently found among the elderly who are mostly dealing with co-morbidities and polypharmacy, were found to be significant in high risk of potential Drug-drug Interactions (pDDIs). Aim: To identify potential drug-drug interactions in ischaemic stroke patients. Materials and Methods: This retrospective study was conducted in the General Medicine Department at Justice KS Hegde Charitable Hospital, Mangaluru, Karnataka, India, from January 2018 to August 2020. All the stroke patient’s data were collected based on the inclusion criterion. Prescriptions were obtained from the case sheets and the pDDIs were identified using UpToDate software. Results: The mean age of the study population (N=350) was found to be 61.07±11.460 years, The incidence of stroke was high in males (66%) than in females (34%) from the total of 350 patients. The prescribing patterns were antiplatelet single (69.4%) and fixed-dose combination (1.42%), anticoagulants (11.14%), antihypertensive agents (63.42%), followed by lipidlowering agents (65.14%) as single and fixed dose combinations (0.85%), gastrointestinal agents (70.57%). The class prescribed the most was antiplatelet agents (aspirin 61.4%). The total number of 402 pDDIs were found among 350 patients. Based on the Lexi-Interact® severity scale moderate interactions were the most commonly found then followed by the major and minor with 301 (74.87%), 66 (16.41%) and 35 (8.70%) respectively. The most frequent interaction found were clopidogrel with pantoprazole, and atorvastatin with clopidogrel with same incidence of in 44 (12.57%) patients. Conclusion: The majority of the interaction was found to be moderate interactions which were followed by major and minor interactions. The pDDIs mostly occurred among the antiplatelet agents, gastro-intestinal agents and antihypertensives.

Chiglitazar, a pan agonist of non-thiazolidinedione peroxisome proliferator-activated receptor, has the potential to regulate blood sugar, improve lipid metabolism, and reduce cardiovascular complications. This study aimed to examine the effect of cytochrome P450 (CYP) 3A4 inhibitors/inducers on the in vivo metabolism of chiglitazar and provide a reference for the clinical combination use of chiglitazar. A single-center, open-label, sequential crossover, and self-control study was carried out in 24 healthy subjects to determine the pharmacokinetics of chiglitazar dosed with and without CYP3A4 inhibitors and inducers. The findings showed that the CYP3A4 inhibitor itraconazole had no apparent pharmacokinetic drug interaction with chiglitazar, whereas rifampicin did. When combined with rifampicin after continuous dosing, chiglitazar exposure was not theoretically reduced but increased compared to a single dose of chiglitazar. The possible explanation may be the transporters of bile salt export pump, but this needs to be confirmed. The safety of chiglitazar in single or combination doses was well tolerated. The findings of this study provide a basis for clinical combinations of chiglitazar with CYP3A4 inhibitors or inducers.

Maribavir, an orally available antiviral agent, has been approved in multiple countries for the treatment of patients with refractory post-transplant cytomegalovirus (CMV) infection and/or disease. Maribavir is primarily metabolized by CYP3A4; coadministration with CYP3A4 inducers and inhibitors may significantly alter maribavir exposure, thereby affecting its efficacy and safety. The effect of CYP3A4 inducers and inhibitors on maribavir exposure was evaluated based on a drug-drug interaction (DDI) study and physiologically-based pharmacokinetic (PBPK) modeling. The effect of rifampin (a strong inducer of CYP3A4 and moderate inducer of CYP1A2), administered at a 600mg dose once daily, on maribavir pharmacokinetics was assessed in a clinical phase1 DDI study in healthy participants. A full PBPK model for maribavir was developed and verified using invitro and clinical pharmacokinetic data from phase1 studies. The verified PBPK model was then used to simulate maribavir DDI interactions with various CYP3A4 inducers and inhibitors. The DDI study results showed that coadministration with rifampin decreased the maribavir maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC), and trough concentration (Ctrough) by 39%, 60%, and 82%, respectively. Based on the results from the clinical DDI study, the coadministration of maribavir with rifampin is not recommended. The PBPK model did not predict a clinically significant effect of CYP3A4 inhibitors on maribavir exposure; however, it predicted that strong or moderate CYP3A4 inducers, including carbamazepine, efavirenz, phenobarbital, and phenytoin, may reduce maribavir exposure to a clinically significant extent, and may prompt the consideration of a maribavir dosing increase, in accordance with local approved labels and/or regulations.

Effect of CYP2D6 genotype on pharmacokinetic interactions with psychotropic drugs

The Impact of Drug Interactions on Outcomes in Ibrutinib-Treated Patients with Chronic Lymphocytic Leukemia in Routine Clinical Care: A Population-Based Cohort Study

Endogenous metabolites of cytochrome P450 (CYP3A) are useful in predicting drug-drug interactions between in vivo CYP3A inhibitors and inducers for clinical applications of CYP3A substrate drugs. This study aimed to develop predictable markers of the magnitude of hepatic CYP3A induction and inhibition in healthy female subjects using pharmacometabolomics. Twelve female subjects received midazolam during three study phases: 1mg midazolam (control phase), 1mg midazolam after pretreatment with 400mg ketoconazole once daily for 4days (CYP3A inhibition phase), and 2.5mg midazolam after pretreatment with 600mg rifampicin once daily for 10days (CYP3A induction phase). Throughout the study, blood samples were collected 24h after midazolam administration and urine samples at 12-h intervals during the 24h before and after midazolam administration for the analysis of endogenous steroid metabolites. A statistical model was generated to predict midazolam clearance using measurements of endogenous metabolites associated with the inhibition and induction of CYP3A. Mean midazolam clearance decreased to ∼20% of control levels during the inhibition phase and increased more than 2-fold during the induction phase. Of the urine and plasma metabolites measured, the 6β-hydroxycortisol/cortisol ratio was most significantly correlated with midazolam clearance during hepatic CYP3A inhibition and induction. Our results suggest that the urinary 6β-hydroxycortisol/cortisol ratio is the best predictor of hepatic CYP3A activity under both maximal inhibition and maximal induction. Furthermore, the predictive model including 6β-hydroxycortisol/cortisol as a covariate could be applied to predict the magnitude of CYP3A-mediated drug interactions.

New therapeutic agents marketed in 2020: Part 1

Presents a case report of a 46-year-old Caucasian nonsmoker, lives at an institution for people with intellectual disabilities He is known to have a severe intellectual disability of unknown cause as well as schizophrenia, for which he takes 200 mg of clozapine twice daily The clozapine trough level at steady state was 553mg/L, the clozapine level/dose (C/D) ratio 1 4, and the clozapine/norclozapine (C/N) ratio 1 7 COVID-19 may be associated with hyper inflammation and extremely severe pneumonia This case illustrates that this can lead to an unexpectedly high increase in the clozapine level, with the danger of intoxication The recommendation to reduce the dosage of clozapine by half is therefore probably not cautious enough Frequent monitoring of the patient for any symptoms of intoxication and monitoring the clozapine levels may help to determine the dose day by day to avoid both underdosing, with the risk of psychotic relapse, and overdosing, with the risk of intoxication Calculating the C/D ratio may help with this (PsycInfo Database Record (c) 2021 APA, all rights reserved)

Pharmacotherapy Modifications Due to Drug Interactions with Concomitant Fungal Prophylaxis and Nontuberculous Mycobacteria Treatment after Transplant

Effect of dexamethasone on direct Xa-inhibitor oral anticoagulant plasma levels in patients with COVID-19