Therapeutic drug monitoring (TDM) of antifungal agents

Amphotericin B (all formulations), fluconazole, terbinafine, caspofungin, micafungin and anidulafungin do not require TDM either for reasons of concentration, efficacy or toxicity. Flucytosine at currently recommended doses (especially in neonates and in those with renal failure) does need monitoring. The triazoles itraconazole, voriconazole and posaconazole should be monitored, if possible. View video " Anti-fungal therapeutic drug monitoring and azole dose modification".

Flucytosine

Flucytosine is best measured in all patients who receive it in the first week of therapy for all patients and in the first 72 hours for neonates and anyone with impaired renal function. Target levels are

Itraconazole

Itraconazole has highly variable pharmacokinetics in adults partly because of non-linear clearance, partly because of variable bioavailability of different preparations and partly because of drug interactions. TDM may be effected using a bioassay or HPLC, with ~10-fold different read-outs because of a bioactive metabolite and bioassay reading (Law, 1994). Target levels by bioassay are 5 - 17.1mg/L and 0.5-4.0 mg/L by HPLC.

Several concentration-effect relationships have been demonstrated with itraconazole. Low levels of <0.5 mg/L are associated with breakthrough invasive fungal infections in neutropenic patients. This roughly translates to a lower level of 5.0 mg/L by bioassay. Increasing plasma concentrations are associated with an increasing number of adverse events, rising from 26% frequency at 5 mg/L to 86% at >25mg/L.

Voriconazole

Voriconazole has extremely variable pharmacokinetics in adults (>100-fold) and children justifying TDM. Rapid metabolism in young children and reduced metabolism in older patients, those with hepatic impairment and in those taking omeprazole and other proton-pump inhibitors account for much variation. The genetic polymorphism in Cyp2C19A gene may account for up to 30% of variation.  Drug interactions also contribute to variation.  Pre-dose level target range is 1.3 - 5.7mg/L.

A ‘no effect’ random plasma level is <0.25 mg/L, with improved rates if concentrations are 3 - 4 mg/L Dose escalation should be cautious in adults because of non-linear kinetics, unless levels are very low. Immediate stopping of voriconazole at plasma concentrations >6.0mg/L is strongly recommended because of an increased potential for life-threatening and serious adverse events with restarting therapy at a lower dose once levels have fallen into the desired therapeutic range.

Posaconazole

Studies of posaconazole plasma levels in ill adults and children demonstrated large variations between individuals reflecting absorption probably. Target plasma levels are 0.7-1.3mg/L. Concentration-dependant adverse effects are not described with posaconazole. If levels are low are splitting dosing from 400mg twice daily to 200mg four times daily and increasing fatty food or drink with posaconazole usually is effective, except in highly immunocompromised patients.