Absence Of Drug-drug Interactions Research Articles

Abstract P3-07-15: Preliminary data from a Phase 1b dose escalation study of OP-1250, an oral CERAN, in combination with palbociclib in patients with advanced and/or metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer

Abstract Background: OP-1250 is a small molecule oral complete estrogen receptor antagonist (CERAN) that binds the ligand binding domain of the ER and completely blocks ER-driven transcriptional activity. CDK4/6 inhibitors in combination with endocrine therapy have improved progression free survival and overall survival for patients (pts) with metastatic breast cancer (MBC) in the first- and second-line settings. However, most patients will progress and newer combinations such as with OP-1250 may provide improved clinical outcome. OP-1250 potently inactivates both wild-type ER and mutant forms of ER. The latter confers ligand independent activity and is a mechanism of resistance to standard of care endocrine therapies. In preclinical studies, OP-1250 in combination with palbociclib demonstrated synergistic activity in models of wild-type ER and those containing ESR1 activating mutations, and in models of brain metastasis. A Phase 1/2 monotherapy study of OP-1250 is ongoing in MBC subjects who have received 1 or more prior endocrine therapies (NCT04505826). Monotherapy is well tolerated and the recommended phase 2 dose is 120 mg QD. The aim of this combination trial is to define the maximum tolerated dose (MTD), safety, tolerability, and pharmacokinetics (PK) of OP-1250 in combination with palbociclib. Methods: Eligibility criteria include pts with MBC or locally advanced breast cancer who have received no more than 1 prior line of endocrine therapy (prior CDK4/6 inhibitors and one line of chemotherapy are permitted) and measurable or non-measurable disease. Using a 3+3 design, cohorts are sequentially enrolled, and pts receive escalating doses of OP-1250 orally QD continuously in combination with 125 mg of palbociclib orally for 21 of 28 days. Pts are evaluable for dose limiting toxicities (DLTs) if >75% of both treatments were administered within the first 28-day treatment cycle. Blood is collected for PK on cycle 1 days 1, 2 and cycle 2 days 15, 16 for OP-1250 and cycle 1 day 15 for palbociclib. PK profiles, exposure parameters, and drug-drug interactions (DDIs) are assessed. Pts are monitored for adverse events (AE) and tumor assessments (RECIST 1.1) are conducted every two cycles. Results: As of July 7, 2022, 9 pts were evaluable for DLTs after 28 days of treatment in dose levels 30 mg, 60 mg, and 90 mg of OP-1250 in combination with palbociclib. No DLTs occurred at any of the dose levels. As of May 13, 2022, of the 7 pt safety data set, the most common Grade 1/2 treatment emergent adverse events (TEAE), which occurred in 2 patients, were nausea, gastroesophageal reflux, vomiting, and fatigue. Grade 3 neutropenia occurred in 4 pts and all were attributed to palbociclib by the investigator. No Grade 4 events were observed. OP-1250 was highly bioavailable and showed dose proportional exposure in combination with palbociclib. The single and multiple dose exposure of OP-1250 was consistent with that observed in the monotherapy study, indicating an absence of effect of palbociclib on OP-1250 PK. 90 mg steady-state evaluation is ongoing. Palbociclib concentrations at steady state did not demonstrate a meaningful difference from published exposure parameters for the three dose levels evaluated, indicating an absence of DDI. Conclusions: In the first three cohorts of OP-1250 and palbociclib, the combination was well tolerated and no DLTs occurred. There were no clinically significant DDIs observed between OP-1250 and palbociclib at the doses evaluated and exposure of each drug was consistent with observed monotherapy exposure levels. Dose escalation of OP-1250 continues to 120 mg, to be followed by dose expansion. Updated data will be presented. (NCT05266105) Citation Format: Arlene Chan, Daphne Day, Rina Hui, Nicole McCarthy, Rosalind Wilson, Demiana Faltaos, Morena Shaw, Caitlin Murphy. Preliminary data from a Phase 1b dose escalation study of OP-1250, an oral CERAN, in combination with palbociclib in patients with advanced and/or metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-15.

Біль, тривога, порушення сну — три мішені для прегабаліну при нейропатичних болях в спині

Стаття присвячена перевагам прегабаліну (препарат Судорега®) як засобу першої лінії медикаментозної терапії пацієнтів із хронічними нейропатичними болями в спині. Аналгезуючий ефект препарату в поєднанні зі здатністю коригувати порушення сну і психоемоційного стану дозволяє досягти терапевтичного успіху навіть при тяжких, резистентних до традиційної терапії формах захворювання. Серед інших переваг препарату Судорега® — високий профіль безпеки, відсутність міжлікарських взаємодій, що дозволяють застосовувати його в пацієнтів із поліморбідністю, в осіб похилого віку; цінова доступність.

Absence of drug-drug interactions between γ-hydroxybutyric acid (GHB) and cobicistat.

Potential interactions between CYP3A4 inhibitors and γ-hydroxybutyric acid (GHB) have been suggested as a possible explanation for cases of GHB overdose in recent years among people living with HIV engaged in chemsex. Our objective was to assess the effect of cobicistat on the pharmacokinetics of GHB. Fifteen healthy adults were enrolled in this randomized, double-blind, placebo-controlled, two-arm, crossover clinical trial. Participants underwent two 5 day treatment periods with at least a 1 week washout period between them. In each treatment period, participants received cobicistat (150 mg q24h orally) or matched placebo. On day 5 of each treatment period, participants were given a single oral dose of GHB (25 mg/kg). Plasma concentrations of GHB, subjective effects, blood pressure, heart rate and oxygen saturation were monitored for 5 h after dosing. GHB pharmacokinetic and pharmacodynamic parameters were calculated for each participant during each study period by non-compartmental analysis and were compared using linear mixed-effects models. The study was registered at https://www.clinicaltrialsregister.eu (Eudra-CT number 2019-002122-71) and at https://clinicaltrials.gov (NCT04322214). Ten participants completed the two study periods. No drug-related adverse events that necessitated subject withdrawal or medical intervention occurred during the study. Compared with placebo, none of the primary pharmacokinetic parameters of GHB was substantially changed by the administration of GHB with cobicistat. Similarly, no differences regarding subjective or physiological effects were observed when GHB was administered alone or with cobicistat. Neither pharmacokinetic nor pharmacodynamic drug-drug interactions between cobicistat and GHB were identified in this study.

Physiologically based pharmacokinetic modelling of oxycodone drug-drug interactions.

Oxycodone is an opioid analgesic with several pharmacologically active metabolites and relatively narrow therapeutic index. Cytochrome P450 (CYP) 3A4 and CYP2D6 play major roles in the metabolism of oxycodone and its metabolites. Thus, inhibition and induction of these enzymes may result in substantial changes in the exposure of both oxycodone and its metabolites. In this study, a physiologically based pharmacokinetic (PBPK) model was built using GastroPlus™ software for oxycodone, two primary metabolites (noroxycodone, oxymorphone) and one secondary metabolite (noroxymorphone). The model was built based on literature and in house in vitro and in silico data. The model was refined and verified against literature clinical data after oxycodone administration in the absence of drug-drug interactions (DDI). The model was further challenged with simulations of oxycodone DDI with CYP3A4 inhibitors ketoconazole and itraconazole, CYP3A4 inducer rifampicin and CYP2D6 inhibitor quinidine. The magnitude of DDI (AUC ratio) was predicted within 1.5-fold error for oxycodone, within 1.8-fold and 1.3-4.5-fold error for the primary metabolites noroxycodone and oxymorphone, respectively, and within 1.4-4.5-fold error for the secondary metabolite noroxymorphone, when compared to the mean observed AUC ratios. This work demonstrated the capability of PBPK model to simulate DDI of the administered compounds and the formed metabolites of both DDI victim and perpetrator. However, the predictions for the formed metabolites tend to be associated with higher uncertainty than the predictions for the administered compound. The oxycodone model provides a tool for forecasting oxycodone DDI with other CYP3A4 and CYP2D6 DDI perpetrators that may be co-administered with oxycodone.

Drug-Drug Interactions of 257 Antineoplastic and Supportive Care Agents With 7 Anticoagulants: A Comprehensive Review of Interactions and Mechanisms.

Data on drug–drug interactions (DDI) of antineoplastic drugs with anticoagulants is scarce. We aim to evaluate factors associated with DDI of antineoplastic and supportive care drugs with anticoagulants resulting in modification of pharmacokinetics of these last mentioned. A literature review on DDI databases and summaries of products characteristics (SmPC) was done. Drug–drug interactions of 257 antineoplastic and supportive care drugs with direct oral anticoagulants (DOACs), warfarin, enoxaparin, or fondaparinux were categorized as no clinically significant expected DDI, potentially weak DDI, potentially clinically significant DDI, and recommendation against coadministration. Logistic regression models were performed to analyze the association between the dependent variable potentially clinically significant interaction/recommendation against coadministration and the mechanisms of DDI. Of the 1799 associations, 84.4% were absence of DDI, 3.6% potentially weak DDI, 10.2% potentially clinically relevant DDI, and 2.0% recommendation against coadministration. Warfarin has higher DDI potential than other anticoagulants. Enoxaparin and fondaparinux have fewer DDI than others. There was no difference between DOACs. Drug–drug interactions with apixaban and rivaroxaban was independently associated with the absence of CYP3A4 competition, P-glycoprotein inhibition, CYP3A4 induction, and drug class of tyrosine kinase inhibitors. Drug–drug interactions with dabigatran and edoxaban was associated with inhibition of P-glycoprotein and tyrosine kinase inhibitors. Warfarin, induction of CYP3A4, and inhibition of CYP2C9. Enoxaparin and fondaparinux, only tyrosine kinase inhibitors. Direct oral anticoagulants did not differ regarding DDI with antineoplastic agents. Warfarin presented more DDI than other anticoagulants. P-glycoprotein inhibition and CYP3A4 induction were independently associated with DDI of antineoplastic agents with DOACs.

Lack of Fetal Harm and Absence of Drug-Drug Interactions Attributed to Unique Pharmacokinetic Properties of Mipomersen

Lack of Fetal Harm and Absence of Drug-Drug Interactions Attributed to Unique Pharmacokinetic Properties of Mipomersen

Homeopathic Medications as Clinical Alternatives for Symptomatic Care of Acute Otitis Media and Upper Respiratory Infections in Children

The public health and individual risks of inappropriate antibiotic prescribing and conventional over-the-counter symptomatic drugs in pediatric treatment of acute otitis media (AOM) and upper respiratory infections (URIs) are significant. Clinical research suggests that over-the-counter homeopathic medicines offer pragmatic treatment alternatives to conventional drugs for symptom relief in children with uncomplicated AOM or URIs. Homeopathy is a controversial but demonstrably safe and effective 200-year-old whole system of complementary and alternative medicine used worldwide. Numerous clinical studies demonstrate that homeopathy accelerates early symptom relief in acute illnesses at much lower risk than conventional drug approaches. Evidence-based advantages for homeopathy include lower antibiotic fill rates during watchful waiting in otitis media, fewer and less serious side effects, absence of drug-drug interactions, and reduced parental sick leave from work. Emerging evidence from basic and preclinical science research counter the skeptics' claims that homeopathic remedies are biologically inert placebos. Consumers already accept and use homeopathic medicines for self care, as evidenced by annual US consumer expenditures of $2.9 billion on homeopathic remedies. Homeopathy appears equivalent to and safer than conventional standard care in comparative effectiveness trials, but additional well-designed efficacy trials are indicated. Nonetheless, the existing research evidence on safety supports pragmatic use of homeopathy in order to “first do no harm” in the early symptom management of otherwise uncomplicated AOM and URIs in children.

Dipeptidylpeptitase-4 Inhibitors (Gliptins)

Patients with type 2 diabetes mellitus (T2DM) are generally treated with many pharmacological compounds and are exposed to a high risk of drug-drug interactions. Indeed, blood glucose control usually requires a combination of various glucose-lowering agents, and the recommended global approach to reduce overall cardiovascular risk generally implies administration of several protective compounds, including HMG-CoA reductase inhibitors (statins), antihypertensive compounds and antiplatelet agents. New compounds have been developed to improve glucose-induced beta-cell secretion and glucose control, without inducing hypoglycaemia or weight gain, in patients with T2DM. Dipeptidylpeptidase-4 (DPP-4) inhibitors are novel oral glucose-lowering agents, which may be used as monotherapy or in combination with other antidiabetic compounds, metformin, thiazolidinediones or even sulfonylureas. Sitagliptin, vildagliptin and saxagliptin are already on the market, either as single agents or in fixed-dose combined formulations with metformin. Other compounds, such as alogliptin and linagliptin, are in a late phase of development. This review summarizes the available data on drug-drug interactions reported in the literature for these five DDP-4 inhibitors: sitagliptin, vildagliptin, saxagliptin, alogliptin and linagliptin. Possible pharmacokinetic interferences have been investigated between each of these compounds and various pharmacological agents, which were selected because there are other glucose-lowering agents (metformin, glibenclamide [glyburide], pioglitazone/rosiglitazone) that may be prescribed in combination with DPP-4 inhibitors, other drugs that are currently used in patients with T2DM (statins, antihypertensive agents), compounds that are known to interfere with the cytochrome P450 (CYP) system (ketoconazole, diltiazem, rifampicin [rifampin]) or with P-glycoprotein transport (ciclosporin), or agents with a narrow therapeutic safety window (warfarin, digoxin). Generally speaking, almost no drug-drug interactions or only minor drug-drug interactions have been reported between DPP-4 inhibitors and any of these drugs. The gliptins do not significantly modify the pharmacokinetic profile and exposure of the other tested drugs, and the other drugs do not significantly alter the pharmacokinetic profile of the gliptins or exposure to these. The only exception concerns saxagliptin, which is metabolized to an active metabolite by CYP3A4/5. Therefore, exposure to saxagliptin and its primary metabolite may be significantly modified when saxagliptin is coadministered with specific strong inhibitors (ketoconazole, diltiazem) or inducers (rifampicin) of CYP3A4/5 isoforms. The absence of significant drug-drug interactions could be explained by the favourable pharmacokinetic characteristics of DPP-4 inhibitors, which are not inducers or inhibitors of CYP isoforms and are not bound to plasma proteins to a great extent. Therefore, according to these pharmacokinetic findings, which were generally obtained in healthy young male subjects, no dosage adjustment is recommended when gliptins are combined with other pharmacological agents in patients with T2DM, with the exception of a reduction in the daily dosage of saxagliptin when this drug is used in association with a strong inhibitor of CYP3A4/A5. It is worth noting, however, that a reduction in the dose of sulfonylureas is usually recommended when a DPP-4 inhibitor is added, because of a pharmacodynamic interaction (rather than a pharmacokinetic interaction) between the sulfonylurea and the DPP-4 inhibitor, which may result in a higher risk of hypoglycaemia. Otherwise, any gliptin may be combined with metformin or a thiazolidinedione (pioglitazone, rosiglitazone), leading to a significant improvement in glycaemic control without an increased risk of hypoglycaemia or any other adverse event in patients with T2DM. Finally, the absence of drug-drug interactions in clinical trials in healthy subjects requires further evidence from large-scale studies, including typical subjects with T2DM - in particular, multimorbid and geriatric patients receiving polypharmacy.

Etravirina en primeras líneas de tratamiento

Etravirine (ETR) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with a potent and broad in vitro spectrum of activity against HIV-1 and viruses with NNRTI resistances, allowing sequential use of drugs of this family. The potency, efficacy and safety of etravirine have been demonstrated in multi-treated patients, but few data are available on first-line antiretroviral therapy (ART) and the role of this drug in initial treatment phases has not been defined. The presence of primary NNRTI resistances and those acquired during first-line therapy is increasingly frequent. Due to its genetic barrier and efficacy, ETR can form part of a second-line ART regimen in patients with failure to a first-line regimen. In the initial phases, adverse effects continue to be the main reason for modifying ART. ETR has demonstrated safety and tolerability, with no central nervous system adverse effects and a good liver, lipid and gastrointestinal safety profile. As with the other NNRTIs, the most common adverse effect is rash. Because of ETR good tolerability profile, this drug can be considered when a new treatment is required due to adverse effects. Because of the characteristics of ETR the possibility of once-daily administration and dissolution in water, as well as the absence of drug-drug interactions with methadone this drug is especially attractive as a firstline therapy and in patients with poor adherence, such as intravenous drug users receiving methadone treatment.

Investigation of sarizotan’s impact on the pharmacokinetics of probe drugs for major cytochrome P450 isoenzymes: a combined cocktail trial

The 5HT(1A) receptor agonist sarizotan is in clinical development for the treatment of dyskinesia, a potentially disabling complication in Parkinson's disease. We investigated the effect of sarizotan on the clinical pharmacokinetics of probe drugs for cytochrome P450 (CYP) to evaluate the risk of CYP-related drug-drug interactions. This was a double-blind, randomised, two-period cross-over interaction study with repeated administration of 5 mg sarizotan HCl or placebo b.i.d. for 8 days in 18 healthy volunteers. On day 4, a single dose of 100 mg metoprolol (CYP2D6 probe) was administered. On day 8, single doses of 100 mg caffeine (CYP1A2 probe), 50 mg diclofenac (CYP2C9 probe), 100 mg mephenytoin (CYP2C19 probe) and 7.5 mg midazolam (CYP3A4 probe) were simultaneously applied. Pharmacokinetic parameters for probe drugs and their metabolites in plasma and urinary recovery were determined. Concentration-time profiles and pharmacokinetic parameters of all probes and their metabolites remained unchanged after co-administration of sarizotan, compared with placebo. Analysis of variance of the area under the plasma concentration-time curve for probe drugs/metabolites, metabolic ratios and urinary excretion resulted in 90% confidence intervals within the acceptance range (0.8-1.25), indicating the absence of drug-drug interactions. At a dose higher than that intended for clinical use (1 mg b.i.d.), sarizotan had no effect on the metabolism and pharmacokinetics of specific probe drugs for CYP isoenzymes 1A2, 2C19, 2C9, 2D6 and 3A4. Pharmacokinetic interactions with co-administered drugs metabolised by these CYP isoforms are not expected, and dose adjustment of co-administered CYP substrates is not necessary.

A phase I study with CRx-026, a novel dual action agent, in patients (pts) with advanced solid tumors

3073 Background: CRx-026 contains two active pharmaceutical ingredients which, when combined, synergistically blocks cancer cell division by inhibiting two critical elements of the cancer cell’s mechanism for dividing. One component of CRx-026, chlorpromazine, inhibits hsEg5/KSP, a mitotic kinesin essential for centrosome separation. The other component, pentamidine, is reported to inhibit PRL phosphatases, which play an important role in regulating mitotic progression and proper chromosome separation. The objectives of this Phase I study were to assess the dose limiting toxicities (DLTs), to determine the maximum tolerated dose (MTD), and to describe the pharmacokinetics (PK) of CRx-026 in patients with advanced solid tumors. Methods: 18pts with metastatic cancer whose tumors had progressed on at least one prior therapy were enrolled in escalating dose-level (DL) cohorts in a ‘3+3’ design. The pts received CRx-026 by infusion daily for 5 consecutive days. After a 16-day therapy-free interval (one cycle) the treatment was repeated. Evaluation for response was performed every 2 cycles. EKG monitoring and PK analysis were done during cycle one only. Results: Standard Phase I eligibility criteria were required for patient entry. The pts (median age: 61yrs; 13M/5F) were treated at 4DLs: DL1 (7pts); DL2 (3pts); DL3 (6pts); DL4 (2pts). WHO PS: 0 (7pts.), 1 (11pts.). The DLTs included one dystonic reaction and one supraventricular tachycardia at DL4. The other common toxicity was somnolence which occurred during the infusion but this was not dose limiting. No CRs or PRs have been observed to date. 6pts have shown stable disease ranging from 4–8+ cycles. The median duration on study showed a trend toward longer duration at higher dose levels. The MTD for this trial is DL 3. The PK profile of CRx-026 was linear over the dose range studied. The PK parameters of the components of CRx-026 did not appear to differ from known literature values indicating an absence of drug-drug interactions. Conclusions: CRx-026 represents a different approach to hitting a pattern of targets in cancer cells. CRx-026 can be safely given in pts with advanced cancer. DL3 is the recommended Phase II dose on this schedule to assess its clinical activity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration CombinatoRx CombinatoRx CombinatoRx CombinatoRx