A review of pharmacokinetic drug interactions between antimicrobial and antiseizure medications in children

Abstract

Comorbidity between epilepsy and infectious diseases in children is frequent. Pharmacokinetic drug-drug interactions (DDIs) between antiseizure medications (ASMs) and anti-infectives can occur and influence their efficacy or cause toxicity. All potential DDIs between ASMs and antimicrobial agents used in children were identified through consultation of drug compendia. Clinical studies, case reports and summaries of product characteristics of all identified drugs were also searched. A typical example of a DDI that is often observed in children is that involving valproate (VPA) and carbapenem antibiotics. This DDI has a unique mechanism of action (inhibits the enzyme that catalyses the hydrolysis of VPA-glucuronide) and leads to a fall of around 60% of VPA level, associated with seizure recurrence. An example of bidirectional DDI involves the antimycotic voriconzole and several ASMs. Voriconazole is metabolized and is a strong inhibitor of cytochrome (CYP)3A4, CYP2C9/10 and CYP2C19. There is clinical evidence of induction of voriconazole metabolism with possible loss of its efficacy by phenytoin (PHT), while voriconazole increases the levels of PHT. Other ASMs that are inducers of these enzymes, such as carbamazepine (CBZ), phenobarbital, stiripentol and to a lesser degree, oxcarbazepine, might be predicted to decrease the level of voriconazole. Voriconazole might also be predicted to increase levels of cannabidiol, CBZ, lacosamide, midazolam, and zonisamide. DDIs between ASMs and some antiviral agents are potentially even more frequent and clinically relevant.

Pharmacokinetics and safety of two Voriconazole formulations after intravenous infusion in two doses in healthy Chinese subjects

“…Following oral administration, Voriconazole is rapidly and almost completely absorbed, with C max occurring 1–2 h after dosing. The absolute bioavailability in adults is estimated to be 96%, thus a switch between the intravenous and oral administration is feasible [ 16 , 17 ]. In the 4 mg/kg group, the %AUC ex (first cycle and second cycle) of subjects with random number 1018 was greater than 20%, and the terminal phase elimination rate λ z cannot be accurately estimated, so the PK parameters of the subject are excluded in this test(λ z , AUC 0-∞ , T 1/2 , Cl, V Z , %AUC ex and AUC 0-t ).…”

Therapeutic and Toxic Effects of Valproic Acid Metabolites

“…However, glucuronide conjugation is the predominant pathway for the metabolism and excretion of VPA [ 48 ]. Approximately 20–70% of VPA is excreted in the urine as glucuronide conjugates.…”

“…The metabolism of VPA is complicated and continues to be studied. Known pathways of VPA metabolism include: β-oxidation in the tricarboxylic acid cycle (acetylation); oxidation with the participation of cytochrome P-450 isoenzymes (P-oxidation); and glucuronidation [ 19 , 48 , 49 ]. The complex metabolism of VPA explains the diversity of its active and inactive metabolites, which have therapeutic, neutral, or toxic effects.…”

Pharmacokinetic Interactions Between Antiseizure and Psychiatric Medications

“…The majority of clinically relevant DDIs between antiseizure and psychiatric drugs occur at the oxidative metabolism level and usually involve the cytochrome CYP system or, to a lesser extent, glucuronidation by UGT or changes in drug distribution across membranes by transmembrane polypeptides, including P-glycoprotein (P-gp) [ 11 , 12 ].…”