Safety, Efficacy and Pharmacokinetics of Anidulafungin in Patients 1 Month to <2 Years of Age With Invasive Candidiasis, Including Candidemia.

Nineteen patients 1 month to <2 years of age with (n = 16) or at high risk of (n = 3) invasive candidiasis received anidulafungin for 5-35 days (3 mg/kg day 1, 1.5 mg/kg daily thereafter) followed by optional fluconazole (NCT00761267). Most treatment-emergent adverse events were mild/moderate, and no treatment-related deaths occurred. End of intravenous therapy global response success rate was 68.8%. Pharmacokinetics were similar to adult patients.

Candida species are a common cause of invasive fungal infection in hospitalized patients, including children.[1] Invasive candidiasis (IC) has been associated with excessive mortality and long-term sequelae in infants.[2] Anidulafungin is an echinocandin antifungal drug licensed in adults for the treatment of candidemia and other forms of Candida infections.[3]

We conducted a prospective, open-label, noncomparative, multicenter, international study (NCT00761267) to evaluate the safety, efficacy and pharmacokinetics (PKs) of anidulafungin for the treatment of IC, including candidemia, in pediatric patients 1 month to <18 years of age. Data in patients 2 to <18 years of age from this study have been published previously.[4] Here, we report data for anidulafungin in patients 1 month to <2 years of age, including the results of PK subanalyses of anidulafungin and polysorbate 80 (PS80)—a solubilizing agent for anidulafungin.

MATERIALS AND METHODS

The study design is presented in Figure 1. Patients with IC, 1 month to <18 years of age, were enrolled from June 2009 to February 2018. Full inclusion and exclusion criteria were published previously.[4] The inclusion criteria were revised to permit the participation of patients at high risk for IC (without microbiologically confirmed IC) to facilitate enrollment of patients in the 1 month to <2 years of age group. Additionally, exclusion criteria were amended to allow the enrollment of patients who received prior systemic antifungal therapy and patients for whom removal of an infected catheter was undesirable.

FIGURE 1.

Study design.

The study was conducted in compliance with the Declaration of Helsinki and Good Clinical Practice Guidelines established by the International Council for Harmonization. Written consent from parents or legal guardians was obtained.

All patients received a 3 mg/kg loading dose of intravenous (IV) anidulafungin on day 1, followed by a maintenance dose of 1.5 mg/kg daily (both infused at ≤1.1 mg/min) administered for ≤35 days. An optional switch to oral fluconazole (6–12 mg/kg/d, maximum 800 mg/d) was allowed up to a maximum total treatment duration (anidulafungin plus oral fluconazole) of 49 days. This switch was permitted after a minimum of 10 days of anidulafungin in patients with microbiologically confirmed IC. Patients at high risk of IC (without microbiologically confirmed IC) could be switched to oral fluconazole after a minimum of 5 days.

The primary objective[4] was to assess the safety and tolerability of anidulafungin in children with IC. Secondary objectives included global response at end of IV therapy (EOIVT), end of treatment, and at the week 2 and week 6 follow-up visits.[4] We also assessed relapse and new infection rates, at the week 2 and week 6 follow-up visits, and all-cause mortality throughout the study. Additionally, we examined the PK of anidulafungin and PS80. The first 6 patients were included in a PK substudy with serial PK samples collected on days 1 and 2 and analyzed using noncompartmental methods to confirm the dosage regimen. Serial blood samples were collected at 6 time points on days 1 and 2: 2 minutes before the end of infusion on day 1 (receiving 3 mg/kg); and, on day 2 (receiving 1.5 mg/kg), just before the start of infusion, 2 minutes before the end of infusion, and 6, 12 and 24 hours after the start of infusion.

Plasma samples were stored at −20°C or colder after collection and analyzed periodically at a centralized laboratory (PPD, Richmond, VA) using a validated high-performance liquid chromatography–tandem mass spectrometric method. The bioanalytical assay had a dynamic range of 50–20,000 ng/mL and a lower limit of quantification of 50 ng/mL for anidulafungin. The between-day assay accuracy, expressed as percent relative error for quality control (QC) concentrations, ranged from −10.6% to 4.17%. Assay precision, expressed as the between-day percent coefficients of variation (% CV) of the mean estimated concentrations of QC samples, was ≤8.68%.

Blood samples for PS80 measurements were collected from 8 patients following a request from the European Medicines Agency for exposure data of PS80 in infants. Blood samples were collected at 3–5 of the following time points: day 1 (0–2 hours postdose); day 3 (predose); day 5 (0–3 hours postdose); day 7 (6–12 hours delayed postdose); and day 9 (predose).

Plasma samples were stored at −20°C or colder after collection and analyzed periodically at a centralized laboratory (PPD) using a validated high-performance liquid chromatography–tandem mass spectrometric method. The bioanalytical assay had a dynamic range of 5.00–100 µg/mL and a lower limit of quantification of 5.00 µg/mL for PS80. The between-day assay accuracy, expressed as percent relative error, for QC concentrations, ranged from 2.96% to 6.01%. Assay precision, expressed as the between-day % CV of the mean estimated concentrations of QC samples, was ≤11.2%.

Anidulafungin global response was evaluated in the modified intent-to-treat population only (patients who received at least 1 dose of study drug and had confirmed Candida infection). Statistical analyses were mainly descriptive, as detailed previously.[4]

RESULTS

Nineteen patients were enrolled at 13 sites in 7 countries. All were white, 10 (52.6%) were male, and the mean age was 0.9 years (range: 0.1–1.8 years). All received IV anidulafungin and were included in the safety population. Six patients were switched to fluconazole treatment (see Table 1 for treatment durations).

TABLE 1.

Study Treatment Durations and Baseline Characteristics

Sixteen of 19 patients (84.2%) had microbiologically confirmed IC and were included in the modified intent-to-treat population. Baseline pathogen data are summarized in Table 2. The most common site of infection was blood (15/16, 93.8%), and the most common risk factor for IC was the use of broad-spectrum antibiotics, which was reported in all patients (Table 1).

TABLE 2.

Key Results in Patients With IC 1 Month to <2 Years of Age Who Received Anidulafungin

Seventeen of 19 patients (89.5%) exhibited treatment-emergent events (TEAEs) of any causality. TEAEs affecting >20% of the overall safety population are detailed in Table 2. Events were all mild-to-moderate in severity except 10 severe TEAEs reported in 7 patients (36.8%). Of these, 5 were considered serious (abdominal sepsis, coagulopathy, diarrhea, pancytopenia and urinary tract infection), and 1 was considered related to anidulafungin treatment (diarrhea); all resolved. A summary of all-causality TEAEs affecting >5% to ≤20% of patients is in Table 3.

TABLE 3.

Incidence of Treatment-Emergent Adverse Events of All Causalities (Affecting >5% and ≤20% of Safety Population)

Three patients (15.8%) experienced a total of 5 treatment-related TEAEs: diarrhea, pyrexia, increased alanine transaminase, increased aspartate transaminase and erythema. Of these, only diarrhea (serious adverse event in a 3-month-old girl resolved) led to discontinuation of anidulafungin. This event was considered to be anidulafungin related. No patients experienced TEAEs related to fluconazole.

Regarding all-cause mortality, 1 of 19 patients (5.3%) died during the study. The cause of death in this 16-month-old boy was multiple organ dysfunction syndrome on study day 40 which was not considered treatment related.

Eleven of 16 patients (68.8%) achieved a global response of success at EOIVT (Table 2). Responses by the site of infection and by neutrophil count are summarized in Table 4. Two patients (12.5%) with candidemia (1 with Candida albicans and 1 with Candida parapsilosis) had a global response of failure at EOIVT; both had a microbiologic response of persistence at EOIVT (Table 5).

TABLE 4.

Anidulafungin Response Success Rates by Site of Infection and Neutrophil Count at EOIVT (MITT Population)

TABLE 5.

Anidulafungin Response Success Rates (EOIVT) According to Baseline Pathogen (MITT Population)

No patients relapsed or experienced new infection, and 15 of 16 (93.8%) achieved negative blood cultures. The median time to the first negative blood culture was 3 days. No resistance to anidulafungin was observed for Candida species.

Table 2 summarizes anidulafungin PK parameters from the 6 patients included in the PK substudy (age range: 0.1–1.8 years). In addition, plasma concentration of PS80 measured in 28 samples from 8 patients was found to be below the limit of quantification (5 µg/mL) for all samples, except one. A 20-month-old boy with a medical history of increased alanine transaminase and aspartate transaminase had a single PS80 concentration of 5.3 µg/mL, collected 1-hour postloading dose on day 1.

DISCUSSION

We report, to our knowledge, the first comprehensive prospective study of safety, efficacy and PK of anidulafungin in patients 1 month to <2 years of age. Anidulafungin was generally well tolerated in children with IC, or at high risk for IC, at a 3.0 mg/kg loading dose followed by 1.5 mg/kg daily.

Most TEAEs were expected adverse drug reactions or were associated with underlying conditions. TEAEs in patients 1 month to <2 years of age were largely similar to the overall population, although anemia was more commonly reported.[4] Events of anemia were mild-to-moderate in severity and resolved and were not considered treatment related but generally related to the patients’ underlying conditions. No new safety concerns for anidulafungin were identified in patients 1 month to ≤2 years of age.

No deaths were considered related to anidulafungin. All-cause mortality here was lower than previously reported for pediatric patients with IC mainly receiving amphotericin B as initial therapy (up to 24%).[5]

The proportion of patients 1 month to <2 years of age who experienced a global response of success at EOIVT (68.8%) was similar to findings in patients 2 to <18 years of age enrolled within the same study,[4] as well as to that observed in adults (75.6%).[6]

Furthermore, results for anidulafungin exposure in this study were comparable to the reported range of steady-state population PK parameters in adults with fungal infections receiving the standard anidulafungin dose (200 mg loading dose followed by 100 mg maintenance dose): steady-state area under the plasma concentration curve 110.3 mg·h/L (32.5 % CV) and steady-state maximum observed concentration 7.2 mg/L (23.3 % CV).[3] These findings are consistent with a previous PK study in which a loading dose of 3.0 mg/kg and daily maintenance dose of 1.5 mg/kg resulted in similar anidulafungin exposures in neonates and infants <2 years of age.[7]

PS80 exposure was investigated due to a lack of published excipient data in infants, and previous reports of possible hepatotoxicity in neonates and infants associated with other IV drugs formulated with PS80.[8,9] This study is, to our knowledge, the first to evaluate PS80 levels in infants. No hepatotoxicity or PS80 accumulation was detected, and the 1 patient who had a single PS80 concentration above the lower limit of quantification following the loading dose had a medical history of hepatobiliary events. The overall PS80 and anidulafungin PK findings further support anidulafungin use at the studied dose in pediatric patients >1 month of age.

The overall sample size of this study was small, and results should be interpreted with caution. A further limitation was the open-label, noncomparative study design, although this design is common in pediatric studies.[10]

Taken together, the data support the use of anidulafungin 3.0 mg/kg loading dose on day 1, followed by 1.5 mg/kg daily for the treatment of IC, including candidemia, in patients 1 month to <2 years of age.

ACKNOWLEDGMENTS

The authors would like to thank all the investigators and patients from all of the participating sites who made this study possible. The Anidulafungin A8851008 Pediatric Study Group members are as follows: Natalia Dmitrieva, Sandra Arnold, Antonio Arrieta, Fabio Motta, Cheng-Hsun Chiu, Giuseppe Gentile, Chuhl Joo Lyu, Brian Patrick Lee, Vassiliki Syriopoulou, Audra Deveikis, Jaime Deville, Jong Jin Seo, Irina Shipitsina, Nelson Horigoshi, Joan Robinson, Richard Grundy, William Steinbach, Rainer Gedeit and others. All study sites that enrolled patients 1 month to <2 years of age are listed by country as follows: Brazil: Instituto de Oncologia Pediatrica—Grupo de Apoio ao Adolescente e a Crianca com Cancer, São Paulo (Fabianne Carlesse); Hospital Pequeno Principe Curitiba, Paraná (Fabio Motta); and Hospital Infantil Sabara/Fundacao Jose Luiz Egydio Setubal, São Paulo (Nelson Horigoshi); Canada: Stollery Children’s Hospital—University of Alberta, Edmonton, Alberta (Joan Robinson); Greece: Hippokration Hospital, Thessaloniki (Emmanuel Roilides); Italy: Universita degli Studi di Roma La Sapienza, Roma (Giuseppe Gentile); IRCCS Ospedale Pediatrico Bambino Gesu, Roma; Russia: National Cancer Research Center RAMS n.a. N.N. Blokhin, Moscow (Natalia Dmitrieva); United Kingdom: Nottingham Children’s Hospital, Queens Medical Centre, Nottingham (Richard Grundy); and United States: Duke University Medical Center, Durham, North Carolina (William Steinbach); Children’s Hospital of Orange County, Orange, California (Antonio Arrieta); University of California—Los Angeles, Los Angeles, California (Jaime Deville); and Children’s Hospital of Wisconsin, Milwaukee, Wisconsin (Rainer Gedeit). The authors would also like to thank Sakambari Tripathy, who was responsible for overseeing the PS80 assay development and validation, which enabled the analysis and interpretation of anidulafungin and PS80 samples. Medical writing support, under the direction of the authors, was provided by Molly MacFadyen, MSc, and Kimberley Haines, MSc, of CMC Connect, McCann Health Medical Communications, with funding from Pfizer Inc in accordance with Good Publication Practice (GPP3) guidelines.