Voriconazole showed in-vitro activities against Candida ssp., Aspergillus ssp. as well as rarer pathogens like Fusarium ssp. and Scedosporium ssp. [10, 11]. Animal models were mainly conducted in guinea pigs [12]. The EPAR mentions PK/PD indices were investigated by comparing MIC and clinical outcome to mean plasma concentrations in each patient, but claims not to have detected a relationship between efficacy and PK/PD indices. In vivo models of voriconazole show AUC/MIC correlates with efficacy for candidiasis [13, 14].

Most indications (candidiasis, fusariosis and scedosporiosis) were based on pooled efficacy data across the programme and additional data for refractory candidiasis, EC, fusariosis and scedosporiosis where no source could be identified.

The Aspergillus indication was based on a phase II invasive aspergillosis study with a historical control (control: 101 subjects), a phase III invasive aspergillosis study and pooled data across the programme [15, 16].

Voriconazole was initially approved for the treatment of invasive aspergillosis, candidemia in non-neutropenic patients, fluconazole-resistant serious Candida infections and serious fungal infections caused by Scedosporium and Fusarium.

At the time of this review, voriconazole was also approved for the prophylaxis of invasive fungal infections in haematopoietic stem cell transplantation (HSCT) recipients.

Posaconazole was authorised in 2005. In vitro, it was active against various fungi including Aspergillus ssp. and Zygomycetes [17]. The EPAR mentions a correlation between AUC/MIC and efficacy in in vivo models for candidiasis [18]. Additionally, the EPAR claims to have found the same correlation in an analysis of 189 clinical cases.

The clinical evaluation of posaconazole included one phase II study (98 subjects) where we could not determine the indication and therefore could not include it in the table. Phase III consisted of one study including patients that had proven or probable fungal infections refractory to standard treatment. This study used an external control (279 subjects). The majority had Aspergillus infections as well as rarer diseases such as fusariosis, chromoblastomycosis or mycetoma, coccidioidomycosis and cryptococcosis [19]. There was additional data submitted from a pilot study with coccidioidomycosis (20 subjects).

In the end, posaconazole was authorised as second-line medication for invasive aspergillosis, fusariosis, chromoblastomycosis and mycetoma and coccidioidomycosis. Later, this authorisation was broadened to also include oropharyngeal candidiasis in severely sick or immunocompromised patients with little hope to benefit from a topical agent, prophylaxis in patients receiving remission-induction chemotherapy for AML (acute myeloid leukaemia) or MDS (myelodysplastic syndrome), expected to develop neutropenia and in HSCT patients undergoing immunosuppressive therapy for graft-versus-host disease.

Marketed in 2015, isavuconazole is the most recent of the drugs marketed in the last 23 years. Isavuconazole showed promising effect in vitro against Aspergillus ssp. as well as against Mucorales [20, 21]. In terms of the PK/PD relationship, the EPAR describes a correlation between efficacy with the AUC/MIC, although there was no comparison amongst the indices. This information stems from studies of murine pulmonary aspergillosis [22, 23].

Phase II consisted of one study in uncomplicated EC and one study in patients with neutropenia undergoing chemotherapy for AML [24].

The phase III programme included two studies: one double-blind, randomised study comparing isavuconazole with voriconazole in patients with invasive aspergillosis and other filamentous fungi [25]. The other phase III study was an uncontrolled (although the applicant did provide amphotericin B studies in order to compare data), single-arm study including patients with invasive fungal disease caused by rare fungi [26].

These studies led to the authorisation for invasive aspergillosis and for treatment of refractory mucormycosis in adults. The applicant had first sought a first-line indication but changed it to second-line.

To this day, no further authorisation for other indications has been granted.

Caspofungin was the first echinocandin to be launched on the market, in 2001. In in vitro studies it performed very well against azole-susceptible and resistant Candida ssp.as well as other rare moulds including Aspergillus fumigatus and Aspergillus flavus [27, 28]. Animal models were conducted in mice and a pharmacokinetic profile was evaluated in rabbits, as well as in monkeys and rats [29, 30]. Even though pharmacokinetic studies were conducted, there is no mention of a preclinical analysis of PK/PD indices in the EPAR. The EPAR claims two population PK/PD analyses including 142 patients with candidiasis and a similar analysis in patients with aspergillosis were conducted but did not come to a conclusive answer. The applicant committed to further investigate it as part of the post-authorisation measure. Published in 2005, an investigation in mouse models suggested a correlation of efficacy with AUC/MIC for candidiasis as well as Cmax/MEC (minimum effective concentration) for pulmonary aspergillosis [31, 32].

The clinical path included 12 pharmacokinetic studies in phase I (312 subjects) and two phase II studies with refractory extrapulmonary aspergillosis and definite/probable pulmonary aspergillosis that were compared with a historical control (206 subjects). Supportive data came from three phase II studies in EC, additional safety data came from one finished EC trial as well as from two ongoing trials at the time (one trial with invasive candidiasis and one for empirical treatment of fever and neutropenia [33, 34]. A compassionate use study in invasive aspergillosis was also included in the EPAR as the only phase III study, although it included only three patients at that time.

In the end, caspofungin was authorised for the treatment of aspergillosis in patients refractory for amphotericin B.

Additional indications were added on later. At the time of this review, caspofungin was also authorised as treatment for invasive candidiasis in adult and paediatric patients and as empirical therapy for presumed fungal infections in neutropenic adult and paediatric patients.

Anidulafungin was authorised nearly 6 years after caspofungin. As with other echinocandins, it showed promising in vitro effects against Candida ssp. [35]. In models of candidiasis in mice, anidulafungin was very effective [36]. Even though there were animal PK studies investigating the pharmacokinetic properties, no index is mentioned. A population PK/PD analysis was conducted which associated AUC but not AUC/MIC with probabilities of success at global response at the end of therapy and at the 2-week follow-up. Overall, the EPAR considers data too limited to properly characterise the PK/PD index of anidulafungin. In vivo models published in 2008 show a correlation of efficacy with AUC/MIC as well as Cmax/MIC ratios for candidiasis [37].

The phase II studies were conducted in invasive candidiasis [38]. The main phase III study compared anidulafungin and fluconazole [39]. Another study was discontinued due to insufficient enrolment. Further phase II and III studies mentioned in the EPAR were only included in the population pharmacokinetic analysis mentioned above. They were also included in the safety analysis.

Anidulafungin was authorised for the treatment of invasive candidiasis in adult non-neutropenic patients. No further authorised indication has been added to date.

Being the newest member of the echinocandin class, micafungin demonstrates potent in vitro activity against Candida ssp., being fungicidal at MIC and above as well as showing fungistatic but not fungicidal activity against Aspergillus spp. [40]. Although the EPAR does not mention PK/PD indices being investigated, animal models of disseminated Candida infections show a correlation between AUC/MIC and efficacy [41].

The potent activity against Candida ssp. was investigated in phase II and III studies looking at the effect on oesophageal candidiasis and systemic Candida infections [42, 43]. Additionally micafungin was investigated as prophylaxis in a phase III study in patients undergoing HSCT [44].

Micafungin is authorised for treatment of invasive candidiasis patients ≥ 16 years of age, treatment of oesophageal candidiasis in patients aged ≥ 16 years, treatment of invasive candidiasis in children and neonates < 16 years of age and prophylaxis of Candida infection in patients undergoing HSCT or patients who are expected to have neutropenia (absolute neutrophil count < 500 cells/µL) for 10 or more days in adults and children (and neonates) < 16 years of age.

At the time of this review, micafungin has not been authorised for any additional indications.