Oral anticancer agents as generators of relevant pharmacokinetic interactions.

INTRODUCTION: The goal of this paper is to review the impact of marketed oral anticancer agents on the pharmacokinetics of co-administered medications in humans focusing on clinically relevant interactions. METHODS: We identified the oral anticancer agents marketed in the United States and in Europe as December 31, 2021. Based on prescription information and literature, we selected the agents that were moderate/strong inducers or inhibitors of pharmacokinetic human molecular determinants of pharmacological interest (enzymes, drug transporters) highlighting on clinically meaningful interactions (i.e., at least a 2-fold variation in exposure of the comedication, excepting 1.5 for digoxin). RESULTS: As December 31, 2021, 125 marketed oral anticancer agents were identified. Based on a≥2-fold exposure change (≥ 1.5 for digoxin), 24 oral anticancer agents commercialised in the European Union and the United States are susceptible to generate clinically meaningful pharmacokinetic interactions with comedications. All are recent agents and most of them (19/24) are indicated in the treatment of solid tumours. In all, 32 interactions with human molecular kinetic determinants were found for the 24 agents. Most of the pharmacokinetic interactions (26/32) are driven through cytochrome P450 (CYP) inhibition or induction, CYP3A4 being the major contributor (15). CONCLUSION: 24 anticancer agents (20% of the oral market) have the potential to significantly interact with co-administered drugs. These potential pharmacokinetic interactions are likely to occur in the ambulatory setting in a polymedicated and aged population, needing to reinforce the vigilance of community pharmacists and health care providers (particularly in thoracic oncology and genitourinary cancer) with these sometimes rarely prescribed agents.

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.

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.

Clinical Pharmacokinetics and Pharmacodynamics of Dasatinib.

Dasatinib is an oral, once-daily tyrosine kinase inhibitor used in the treatment of chronic myeloid leukaemia and Philadelphia chromosome-positive acute lymphoblastic leukaemia. Dasatinib is rapidly absorbed, with the time for maximal serum concentration varying between 0.25 and 1.5 h. Oral absorption is not affected by food. The absolute bioavailability of dasatinib in humans is unknown due to the lack of an intravenous formulation preventing calculation of the reference exposure. Dasatinib is eliminated through cytochrome P450 (CYP) 3A4-mediated metabolism, with a terminal half-life of 3-4 h. Based on total radioactivity, only 20% of the oral dose (100 mg) is recovered unchanged in faeces (19%, including potential non-absorption) and urine (1%) after 168 h. Dasatinib pharmacokinetics are not influenced by age (children, and adults up to 86 years of age), race and renal insufficiency. Dasatinib absorption is decreased by pH-modifying agents (antacids, H2-receptor blockers, proton pump inhibitors), and dasatinib is also subject to drug interactions with CYP3A4 inducers or inhibitors.

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.

Paralytic ileus possibly associated with interaction between ritonavir/lopinavir and vincristine.

CASE DESCRIPTION: A French Caucasian man aged 39 with HIV infection was treated with abacavir/lamivudine and ritonavir/lopinavir. The patient (normal renal and liver functions) was diagnosed with a Burkitt lymphoma for which he was treated with cyclophosphamide day 1 to 5; doxorubicin day 1; methotrexate day 10; and vincristine day 1 and 8. At day 12, he suffered from abdominal pain associated with constipation. Paralytic ileus was diagnosed by study imaging. Ileus lasted 10 days necessitating parenteral feeding. Later on, a further cycle of chemotherapy with etoposide replacing vincristine was given and was well tolerated. CONCLUSION: We speculate that an interaction between ritonavir/lopinavir and vincristine was responsible for this severe toxicity. Vincristine is transported by P-gp and is metabolized via CYP3A5. Ritonavir is a potent CYP3A5 isoenzyme and P-gp inhibitor. Lopinavir is also a P-gp inhibitor. Ritonavir and lopinavir might have delayed vincristine elimination. Clinicians should be aware of this possible interaction.

Off-label use of anticancer drugs.

Use of a drug outside the terms of its official labelling is referred to as off-label prescription. Many categories of use exist because labelling of anticancer agents is very precise in terms of type or subtype of tumour, association, line, and duration of treatment. Off-label prescription of anticancer drugs is thought to be frequent but, in fact, very few surveys have been done to ascertain its real extent. Findings of prospective studies undertaken between 1990 and 2002 showed proportions of off-label drug use in children and adults of 6.7-33.2%. Most off-label prescription was reported in patients treated with palliative intent, some was associated with clinical benefits, and in specific cancers it formed the standard of care. Off-label use can lead to reimbursement restrictions. Regulatory agencies have created incentives to extend indications for approved drugs to remove them from the off-label area. Proposals have also been made to gather and disseminate accurate and unbiased information on off-label use and to record unapproved indications.

The role of therapeutic drug monitoring in the management of safety of anticancer agents: a focus on 3 cytotoxics.

Introduction: Therapeutic drug monitoring in oncology is used to prevent major toxicities of selected anticancer agents due to overexposure by individualizing the dose based on a pharmacokinetic target. Areas covered: Numerous studies relating a relation between pharmacokinetic variability and toxicity have been reported since the eighties but very few have been implemented in clinical practice due to a lack of validation and harmonization, logistical constraints and reluctance from oncologists. Following recent recommendations, this paper highlights the current-validated applications of pharmacokinetic monitoring in oncology focusing on the safety of anticancer therapies. Expert opinion: Paradoxically given the oldness of the agents, guidelines of dose adjustment have been recently available for intravenous busulfan, 5-fluorouracil, and high-dose methotrexate. Interestingly, besides the enhancement of tolerability, it applies to potential curative clinical situations. In an era of personalized oncology that integrates complex molecular factors in the treatment of cancer, education is needed for oncologists to show the benefits of this valuable (even old) resource for the safety of patients. Therapeutic drug monitoring for busulfan, 5-fluorouracil and methotrexate will still hold in the future unless more active agents are available in the concerned indications.

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.

Evaluation of fixed dosing of new anticancer agents in phase I studies.

AIM: To assess the basis of dosage of investigational anticancer agents in adult phase I trials. MATERIALS AND METHODS: All nonpediatric phase I trials presented at the meetings of the American Society of Clinical Oncology and of the American Society of Hematology in 2005 were reviewed. Data regarding the type of investigational agent, the route of administration and the basis of dosing (fixed, body surface area, body weight) were collected. RESULTS: In all, 225 phase I studies were analyzed concerning 148 new anticancer agents. Among 225 studies, 91 (40.4%) used a fixed dose. Dosages were adjusted to body surface area and body weight in 44% (99/225) and 13.8% (31/225) of all trials, respectively. Regarding drugs given orally (n=40), the majority of the trials (62/77; 80%) used a fixed dose. By contrast, only 7.5% (9/120) of studies involving intravenous agents (n=82) were conducted with a fixed dose. Most of these trials (71.6%) used a dose adjusted to body surface area. Of the 73 trials involving conventional cytotoxics, 70 (96%) used body surface area dosing. On the other hand, 78.5% (62/79) of studies investigating targeted agents used a fixed dose. Monoclonal antibodies and antisense agents were mainly administered on a body weight basis (13/25 and 4/7 trials, respectively). CONCLUSION: A fixed dose was used in a minority of the adult phase I trials presented at the ASCO and ASH meetings in 2005.

[Funding of anticancer drugs in France]. / Modalités de financement des médicaments anticancéreux en France.

This short review presents the modalities of funding of anticancer agents administrated in hospitals in France.

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.

Review. Clinical pharmacokinetics of bortezomib.

This review presents the clinical pharmacokinetics of bortezomib. Aspects regarding metabolism, pharmacodynamics and drug interactions are also discussed.