Dominique Levêque

The Enzymatic Basis of Drug-Drug Interactions with Systemic Triazole Antifungals

Drug-drug interactions are a recurring problem in immunocompromised patients treated with triazole antifungals. While the introduction of new antifungals has expanded opportunities for lowering drug toxicity, virtually all antifungal regimens carry the risk of pharmacokinetic and pharmacodynamic interaction. This review presents the published data on molecular determinants (enzymes, transporters, orphan nuclear receptors) of systemic triazole pharmacokinetics in humans, including itraconazole, fluconazole, voriconazole and posaconazole. Systemic triazoles are inhibitors of cytochrome P450 (CYP) isozymes, such as CYP3A4, CYP2C9 and CYP2C19, to varying degrees. In addition, some are substrates and/or inhibitors of drug transporters such as multidrug resistance-1 gene product, P-glycoprotein, or breast cancer resistance protein. The interactions of triazole antifungals can be divided into the following categories: modifications of antifungal pharmacokinetics by other drugs, modifications of other drug pharmacokinetics by antifungals, and two-way interactions. These features are the basis of most interactions that occur during triazole therapy.

Molecular pharmacokinetics of catharanthus (vinca) alkaloids

This review focuses on the published data regarding the molecular determinants (enzymes, transporters, orphan nuclear receptors) of Catharanthus (vinca) alkaloids pharmacokinetics in humans. The clinical impact of these determinants (drug disposition, drug‐drug interactions) is also discussed.

Drug-Drug Interactions of Triazole Antifungal Agents in Multimorbid Patients and Implications for Patient Care

Drug interactions occur frequently with triazole antifungal agents because of their properties as inhibitors of 1 or more phase 1 (cytochrome P450) biotransformation enzymes and, possibly, as inhibitors or substrates of a phase 2 biotransformation enzyme or transporter protein. Multimorbid patients, including those with hematologic malignancies or other cancers, hematopoietic stem cell or organ transplant recipients, patients infected with the human immunodeficiency virus, and those in the intensive care unit, are at increased risk for drug interactions because they typically require several concomitant medications. They may also be extremely vulnerable to the clinical signs and symptoms of drug interactions. This review describes clinically significant drug interactions most frequently seen in multimorbid patients who receive systemic therapy with triazole antifungals for the prophylaxis or treatment of invasive fungal infections; including interactions with corticosteroids, immunosuppressants, anti-infective drugs, benzodiazepines, opioid analgesics, statins, anticoagulants, anticonvulsants, and drugs affecting gastric pH. The review also describes recommendations concerning contraindications and dose-modification strategies. The azoles differ markedly in their pharmacokinetic and antifungal properties, safety and tolerability, and drug-interaction profiles. Many drug interactions can be prevented if clinicians are thoroughly familiar with the pharmacokinetic profiles of different azoles, follow contraindications and dose-modification recommendations, and switch azoles when possible to achieve the best combination of clinical efficacy and safety. Therapeutic drug monitoring can help optimize treatment and prevent underdosing or overdosing of drugs. Education of patients and their families about signs and symptoms of possible drug interactions is also beneficial.

Adherence to recommendations for the use of antifungal agents in a tertiary care hospital

OBJECTIVES The aim of our study was to assess the adherence to labelling and international guidelines for antifungal prescribing. METHODS A retrospective study was performed in intensive care units in addition to the oncology and haematology department, which covered 70% of antifungal consumption at Hautepierre Hospital, Strasbourg, France. On reviewing medical charts, the antifungal prescription was examined in relation to the recommendations of indication, dosage, risk of drug-drug interactions and, where appropriate, antifungal susceptibility testing. Treatments were considered appropriate, inappropriate or debatable. RESULTS Between January and April 2007, 199 treatments were given for 179 different episodes in 133 adult patients. Treatments were prescribed for pre-emptive or targeted therapy (n = 90, with 60 for candidiasis, 26 for aspergillosis and 4 for other mould diseases), empirical therapy (n = 17) and primary (n = 81) or secondary (n = 11) prophylaxis. Fluconazole accounted for 67% of prescriptions, followed by voriconazole (19%), caspofungin (10%), posaconazole (2%), conventional or liposomal amphotericin B (2%), itraconazole (<1%) and terbinafine (<1%). Indication and dosage were found to be appropriate in 65% and 62% of cases, inappropriate in 22% and 21%, and debatable in 13% and 17%, respectively. The overall (by combining all assessment criteria) rate of inappropriate use was 40%. The overall survival rate at 12 weeks was highest in patients receiving appropriate therapy (81% versus 72% and 68% in the debatable and inappropriate therapy groups, respectively), with between-group differences not being significant (P = 0.49). CONCLUSIONS Our evaluation revealed a high proportion of inappropriate or debatable use of antifungal agents, while highlighting significant issues, such as inadequate dosage or indications.

Clinical Pharmacology of Trastuzumab

Trastuzumab is a monoclonal antibody that targets the extracellular domain of HER2, a member of the epidermal growth factor receptor (EGFR) family. Trastuzumab is currently approved for the treatment of breast cancer overexpressing HER2, given alone or in combination with paclitaxel or docetaxel. Trastuzumab pharmacokinetics are characterized by a low systemic clearance, a low volume of distribution (4l) and a very long half-life (28 days) comparable to that of endogenous immunoglobulins G. The elimination pathways are not yet defined and the clinical relevance of trastuzumab kinetic variability is unknown. Whether exposure might correlate with toxic effects or inadequate response has not been explored. No drug-drug interactions have been reported. This is not surprising because based on the current knowledge, no monoclonal antibody (including trastuzumab) has been found to interact with major molecular pharmacokinetic determinants such enzymes, drug transporters or orphan nuclear receptors. Dosage regimens of trastuzumab are similar either it is used in the adjuvant setting (postoperative) or in metastatic disease. According to the official labelling, trastuzumab is given by intravenous perfusion at a dose based on body weight, weekly (metastatic, adjuvant) or 3-weekly (adjuvant). The schedule also includes a loading dose at the initiation of the treatment. The recommended duration of treatment is currently one year (adjuvant) or until the progression of the disease (metastatic). Regarding the adjuvant setting, different dosage regimens have been tested (from 9 weeks to 2 years) but the optimal duration of treatment is unknown. The short course of trastuzumab (9 weeks) appears promising in terms of activity, tolerance and cost but should be compared to 1 or 2-years treatments. In addition, dosing regimens might be optimized by integrating pharmacokinetic elements. In the adjuvant setting, given the more favorable kinetic situation (absence of tumor penetration), a less intense dosage regimen might be appropriate when compared with that used in metastatic disease. Further body weight is weakly related to trastuzumab exposure and it is not proven that it significantly affects clinical activity. These pharmacokinetic considerations may support the use of fixed doses given monthly, on short periods, for the treatment of early breast cancer.

Pharmacokinetic drug–drug interactions with methotrexate in oncology

Methotrexate is an antifolate agent used in the treatment of various cancers and some autoimmune diseases. In oncology, methotrexate is frequently administered at a high dose (>1 g/m2) and comes with various procedures to reduce the occurrence of toxicity and particularly to ensure optimal renal elimination. Drug–drug interactions involving methotrexate are the origin of severe side effects owing to delayed elimination of the antifolate and, more rarely, of decreased efficacy in relation to suboptimal exposure. Most of these interactions are driven by membrane drug transporters whose activity/expression can be inhibited by the interacting medication. In the last 10 years, research on drug transporters has permitted retrospective identification of the molecular mechanisms underlying drug–drug interactions with methotrexate. This article summarizes reported drug–drug interactions involving methotrexate in clinical oncology with reference to the role of drug transporters that control the disposition of the antifolate agent.

Mécanismes des interactions médicamenteuses d’origine pharmacocinétique

Pharmacokinetic drug-drug interactions occur when a drug alters the disposition (absorption, distribution, elimination) of a coadministered agent. Pharmacokinetic interactions may result in the increase or the decrease of plasma drug concentrations. These modifications are variable in intensity but can lead to contraindications of the association. The mechanisms of pharmacokinetic interactions involve drug metabolizing enzymes, drug transporters and orphan nuclear receptors that regulate at the transcriptional level the expression of enzymes and transporters. The increase of drug plasma concentrations is generally related to the inhibition of enzymes and/or drug transport. The decrease of drug concentrations reflects the activation of orphan nuclear receptors by inducers that lead to the increase of the expression of enzymes and drug transporters. Inhibition of drug metabolism or transport is quite immediate (24-48h) while induction is a slower process (7-10 days). Complex situations may be observed with drugs that are both inducers and inhibitors (rifampin, ritonavir). They can cause the decrease and the increase of the exposure of the combined agent depending on the duration of the association.

Cola beverage and delayed elimination of methotrexate

AIMS To report a case of severe delayed methotrexate elimination attributable to consumption of a cola beverage. METHODS To investigate unexplained low urinary pH in a lymphoma patient treated with high-dose methotrexate. RESULTS Unexpected urinary acidity, despite administration of large amounts of sodium bicarbonate, could be attributed to repeated consumption of a cola beverage. It resulted in a delayed elimination of methotrexate and acute renal failure. Discontinuation of cola drinks, increase in calcium folinate rescue and in sodium bicarbonate allowed satisfactory elimination of methotrexate on day 12 after infusion and recovery from renal impairment without other severe toxicity. No other cause of delay in methotrexate elimination could be identified. CONCLUSIONS Cola beverages have a low pH due to their phosphoric acid content that is excreted by renal route. We recommend patients receiving high dose methotrexate abstain from any cola drink within 24 h before and during methotrexate administration and until complete elimination of the drug.

Rheumatologists’ Perceptions of Biosimilar Medicines Prescription: Findings from a French Web-Based Survey

BackgroundHealthcare cost savings are closely linked to prescribers’ confidence in and acceptance of the prescription of biosimilar drugs.ObjectivesThe aim of this study was to assess the knowledge, experience and opinions of hospital-based and office-based French rheumatologists with regard to biosimilar medicines and to identify the barriers to and possible options to promote their prescription.MethodsA web-based, self-administered survey was conducted among French rheumatologists from June 8 to August 2, 2015.ResultsA total of 116 rheumatologists responded to the survey. Many reported having little knowledge and a lack of available information about biosimilar drugs, especially office-based rheumatologists. 98.3% of the respondents had at least one question about biosimilars, and seven in ten raised issues regarding substitution, iatrogenic effects or cost savings that might be achievable. Only eight rheumatologists had already prescribed a biosimilar drug. The most common barriers reported were indication extrapolation and a lack of data about tolerability. Nine out of ten physicians thought that starting a treatment with a biosimilar drug in biologic treatment-naïve patients was possible. The rheumatologists’ opinions were rather favorable towards the implementation of biosimilars, but a majority expressed a negative opinion about substitution by the pharmacist.ConclusionsOur survey gave a better appreciation of the concerns associated with biosimilar prescriptions. Targeted communication initiatives, deeper experience and availability of new clinical data may help to address the outstanding questions and should overcome the misunderstandings surrounding biosimilar drugs among rheumatologists.

Severe methotrexate toxicity due to a concomitant administration of ciprofloxacin.

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