Caspofungin Acetate

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Caspofungin is an echinocandin antifungal drug [see Microbiology ( 12.4 )]. 12.3 Pharmacokinetics Adult and pediatric pharmacokinetic parameters are presented in Table 8 . Distribution Plasma concentrations of caspofungin decline in a polyphasic manner following single 1-hour IV infusions. A short α-phase occurs immediately postinfusion, followed by a β-phase (half-life of 9 to 11 hours) that characterizes much of the profile and exhibits clear log-linear behavior from 6 to 48 hours postdose during which the plasma concentration decreases 10-fold. An additional, longer half-life phase, γ-phase, (half-life of 40 to 50 hours), also occurs. Distribution, rather than excretion or biotransformation, is the dominant mechanism influencing plasma clearance. Caspofungin is extensively bound to albumin (~97%), and distribution into red blood cells is minimal. Mass balance results showed that approximately 92% of the administered radioactivity was distributed to tissues by 36 to 48 hours after a single 70 mg dose of [ 3 H] caspofungin acetate. There is little excretion or biotransformation of caspofungin during the first 30 hours after administration. Metabolism Caspofungin is slowly metabolized by hydrolysis and N-acetylation. Caspofungin also undergoes spontaneous chemical degradation to an open-ring peptide compound, L-747969. At later time points (≥5 days postdose), there is a low level (≤7 picomoles/mg protein, or ≤1.3% of administered dose) of covalent binding of radiolabel in plasma following single-dose administration of [ 3 H] caspofungin acetate, which may be due to two reactive intermediates formed during the chemical degradation of caspofungin to L-747969. Additional metabolism involves hydrolysis into constitutive amino acids and their degradates, including dihydroxyhomotyrosine and N-acetyl-dihydroxyhomotyrosine. These two tyrosine derivatives are found only in urine, suggesting rapid clearance of these derivatives by the kidneys. Excretion Two single-dose radiolabeled pharmacokinetic studies were conducted. In one study, plasma, urine, and feces were collected over 27 days, and in the second study plasma was collected over 6 months. Plasma concentrations of radioactivity and of caspofungin were similar during the first 24 to 48 hours postdose; thereafter drug levels fell more rapidly. In plasma, caspofungin concentrations fell below the limit of quantitation after 6 to 8 days postdose, while radiolabel fell below the limit of quantitation at 22.3 weeks postdose. After single intravenous administration of [ 3 H] caspofungin acetate, excretion of caspofungin and its metabolites in humans was 35% of dose in feces and 41% of dose in urine. A small amount of caspofungin is excreted unchanged in urine (~1.4% of dose). Renal clearance of parent drug is low (~0.15 mL/min) and total clearance of caspofungin is 12 mL/min. Special Populations Renal Impairment In a clinical study of single 70 mg doses, caspofungin pharmacokinetics were similar in healthy adult volunteers with mild renal impairment (creatinine clearance 50 to 80 mL/min) and control subjects. Moderate (creatinine clearance 31 to 49 mL/min), severe (creatinine clearance 5 to 30 mL/min), and end-stage (creatinine clearance less than 10 mL/min and dialysis dependent) renal impairment moderately increased caspofungin plasma concentrations after single-dose administration (range: 30 to 49% for AUC). However, in adult patients with invasive aspergillosis, candidemia, or other Candida infections (intra-abdominal abscesses, peritonitis, or pleural space infections) who received multiple daily doses of caspofungin 50 mg, there was no significant effect of mild to end-stage renal impairment on caspofungin concentrations. No dosage adjustment is necessary for patients with renal impairment. Caspofungin is not dialyzable, thus supplementary dosing is not required following hemodialysis. Hepatic Impairment Plasma concentrations of caspofungin after a single 70 mg dose in adult patients with mild hepatic impairment (Child-Pugh score 5 to 6) were increased by approximately 55% in AUC compared to healthy control subjects. In a 14-day multiple-dose study (70 mg on Day 1 followed by 50 mg daily thereafter), plasma concentrations in adult patients with mild hepatic impairment were increased modestly (19 to 25% in AUC) on Days 7 and 14 relative to healthy control subjects. No dosage adjustment is recommended for patients with mild hepatic impairment. Adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9) who received a single 70 mg dose of caspofungin had an average plasma caspofungin increase of 76% in AUC compared to control subjects. A dosage reduction is recommended for adult patients with moderate hepatic impairment based upon these pharmacokinetic data [see Dosage and Administration ( 2.4 )]. There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score greater than 9) or in pediatric patients with any degree of hepatic impairment. Gender Plasma concentrations of caspofungin in healthy adult men and women were similar following a single 70 mg dose. After 13 daily 50 mg doses, caspofungin plasma concentrations in women were elevated slightly (approximately 22% in area under the curve [AUC]) relative to men. No dosage adjustment is necessary based on gender. Race Regression analyses of patient pharmacokinetic data indicated that no clinically significant differences in the pharmacokinetics of caspofungin were seen among Caucasians, Blacks, and Hispanics. No dosage adjustment is necessary on the basis of race. Geriatric Patients Plasma concentrations of caspofungin in healthy older men and women (65 years of age and older) were increased slightly (approximately 28% AUC) compared to young healthy men after a single 70 mg dose of caspofungin. In patients who were treated empirically or who had candidemia or other Candida infections (intra-abdominal abscesses, peritonitis, or pleural space infections), a similar modest effect of age was seen in older patients relative to younger patients. No dosage adjustment is necessary for the elderly [see Use in Specific Populations ( 8.5 )] . Pediatric Patients Caspofungin has been studied in five prospective studies involving pediatric patients under 18 years of age, including three pediatric pharmacokinetic studies [initial study in adolescents (12 to 17 years of age) and children (2 to 11 years of age) followed by a study in younger patients (3 to 23 months of age) and then followed by a study in neonates and infants (less than 3 months of age)] [see Use in Specific Populations ( 8.4 )]. Pharmacokinetic parameters following multiple doses of caspofungin in pediatric and adult patients are presented in Table 8 . Table 8: Pharmacokinetic Parameters Following Multiple Doses of Caspofungin in Pediatric (3 months to 17 years) and Adult Patients * Harmonic Mean ± jackknife standard deviation † N=5 for C 1hr and AUC 0-24hr ; N=6 for C 24hr ‡ N=117 for C 24hr ; N=119 for C 1hr § Following an initial 70 mg loading dose on day 1 Population N Daily Dose Pharmacokinetic Parameters (Mean ± Standard Deviation) AUC 0-24hr (mcg∙hr/mL) C 1hr (mcg/mL) C 24hr (mcg/mL) t 1/2 (hr)* CI (mL/min) PEDIATRIC PATIENTS Adolescents, Aged 12 to 17 years 8 50 mg/m 2 124.9 ± 50.4 14.0 ± 6.9 2.4 ± 1.0 11.2 ± 1.7 12.6 ± 5.5 Children, Aged 2 to 11 years 9 50 mg/m 2 120.0 ± 33.4 16.1 ± 4.2 1.7 ± 0.8 8.2 ± 2.4 6.4 ± 2.6 Young Children, Aged 3 to 23 months 8 50 mg/m 2 131.2 ± 17.7 17.6 ± 3.9 1.7 ± 0.7 8.8 ± 2.1 3.2 ± 0.4 ADULT PATIENTS Adults with Esophageal Candidiasis 6 † 50 mg 87.3 ± 30.0 8.7 ± 2.1 1.7 ± 0.7 13.0 ± 1.9 10.6 ± 3.8 Adults receiving Empirical Therapy 119 ‡ 50 mg § -- 8.0 ± 3.4 1.6 ± 0.7 -- -- Drug Interactions [see Drug Interactions ( 7 )] Studies in vitro show that caspofungin acetate is not an inhibitor of any enzyme in the cytochrome P (CYP) system. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for CYP enzymes. In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other drugs. Clinical studies in adult healthy volunteers also demonstrated that the pharmacokinetics of caspofungin are not altered by itraconazole, amphotericin B, mycophenolate, nelfinavir, or tacrolimus. Caspofungin has no effect on the pharmacokinetics of itraconazole, amphotericin B, or the active metabolite of mycophenolate. Cyclosporine : In two adult clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin by approximately 35%. Caspofungin did not increase the plasma levels of cyclosporine. There were transient increases in liver ALT and AST when caspofungin and cyclosporine were co-administered [see Warnings and Precautions ( 5.2 )]. Tacrolimus : Caspofungin reduced the blood AUC 0-12 of tacrolimus (FK-506, Prograf ® ) by approximately 20%, peak blood concentration (C max ) by 16%, and 12-hour blood concentration (C 12hr ) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of caspofungin 70 mg daily, as compared to results from a control period in which tacrolimus was administered alone. For patients receiving both therapies, standard monitoring of tacrolimus whole blood trough concentrations and appropriate tacrolimus dosage adjustments are recommended. Rifampin : A drug-drug interaction study with rifampin in adult healthy volunteers has shown a 30% decrease in caspofungin trough concentrations [see Dosage and Administration ( 2.5 )]. Other Inducers of Hepatic CYP Enzymes Adults : Results from regression analyses of adult patient pharmacokinetic data suggest that co-administration of other hepatic CYP enzyme inducers (e.g., efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine) with caspofungin may result in clinically meaningful reductions in caspofungin concentrations. It is not known which drug clearance mechanism involved in caspofungin disposition may be inducible [see Dosage and Administration ( 2.5 )]. Pediatric patients: In pediatric patients, results from regression analyses of pharmacokinetic data suggest that co-administration of dexamethasone with caspofungin may result in clinically meaningful reductions in caspofungin trough concentrations. This finding may indicate that pediatric patients will have similar reductions with inducers as seen in adults [see Dosage and Administration ( 2.5 )]. 12.4 Microbiology Mechanism of Action Caspofungin, an echinocandin, inhibits the synthesis of beta (1,3)-D-glucan, an essential component of the cell wall of susceptible Aspergillus species and Candida species. Beta (1,3)-D-glucan is not present in mammalian cells. Caspofungin has shown activity against Candida species and in regions of active cell growth of the hyphae of Aspergillus fumigatus . Resistance There have been reports of clinical failures in patients receiving caspofungin therapy due to the development of drug resistant Candida or Aspergillus species. Some of these reports have identified specific mutations in the Fks subunits, encoded by the fks 1 and/or fks 2 genes, of the glucan synthase enzyme. These mutations are associated with higher MICs and breakthrough infection. Candida species that exhibit reduced susceptibility to caspofungin as a result of an increase in the chitin content of the fungal cell wall have also been identified, although the significance of this phenomenon in vivo is not well known. Interaction With Other Antimicrobials Studies in vitro and in vivo of caspofungin, in combination with amphotericin B, suggest no antagonism of antifungal activity against either A. fumigatus or C. albicans . The clinical significance of these results is unknown. Antimicrobial Activity Caspofungin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections [see Indications and Usage ( 1