CLINICAL PHARMACOLOGY
Pharmacokinetics
Absorption
Posaconazole is absorbed with a median Tmax of ~3 to 5 hours. Dose proportional increases in plasma exposure (AUC) to posaconazole were observed following single oral doses from 50 mg to 800 mg and following multiple-dose administration from 50 mg BID to 400 mg BID. No further increases in exposure were observed when the dose was increased from 400 mg BID to 600 mg BID in febrile neutropenic patients or those with refractory invasive fungal infections. Steady-state plasma concentrations are attained at 7 to 10 days following multiple-dose administration.
Following single-dose administration of 200 mg, the mean AUC and Cmax of posaconazole are approximately 3 times higher when administered with a nonfat meal and approximately 4 times higher when administered with a high-fat meal (~50 gm fat) relative to the fasted state. Following single-dose administration of 400 mg, the mean AUC and Cmax of posaconazole are approximately 3 times higher when administered with a liquid nutritional supplement (14 gm fat) relative to the fasted state (see TABLE 1). In order to assure attainment of adequate plasma concentrations, it is recommended to administer posaconazole with food or a nutritional supplement. (See DOSAGE AND ADMINISTRATION.)
TABLE 1: The Mean (%CV) [min-max] Posaconazole Pharmacokinetic Parameters Following Single-Dose Suspension Administration of 200 mg and 400 mg Under Fed and Fasted Conditions | Dose (mg) | Cmax (ng/mL) | Tmax
(hr) | AUC(I) (ng∙hr/mL) | CL/F (L/hr) | t1/2 (hr) |
|---|
200 mg
fasted (n=20)
| 132 (50)
[45–267] | 3.50
[1.5–36The subject with Tmax of 36 hrs had relatively constant plasma levels over 36 hrs (1.7 ng/mL difference between 4 hrs and 36 hrs)] | 4179 (31)
[2705–7269] | 51 (25)
[28–74] | 23.5 (25)
[15.3–33.7] |
200 mg
nonfat (n=20) | 378 (43)
[131–834] | 4 [3–5] | 10,753 (35)
[4579–17,092] | 21 (39)
[12–44] | 22.2 (18)
[17.4–28.7] |
200 mg
high fat
(54 gm fat) (n=20) | 512 (34)
[241–1016] | 5 [4–5] | 15,059 (26)
[10,341–24,476] | 14 (24)
[8.2–19] | 23.0 (19)
[17.2–33.4] |
400 mg
fasted (n=23)
| 121 (75)
[27–366] | 4 [2–12] | 5258 (48)
[2834–9567] | 91 (40)
[42–141] | 27.3 (26)
[16.8–38.9] |
400 mg with
liquid nutritional
supplement
(14 gm fat)(n=23) | 355 (43)
[145–720] | 5 [4–8] | 11,295 (40)
[3865–20,592] | 43 (56)
[19–103] | 26.0 (19)
[18.2–35.0] |
Distribution
Posaconazole has an apparent volume of distribution of 1774 L, suggesting extensive extravascular distribution and penetration into the body tissues.
Posaconazole is highly protein bound (>98%), predominantly to albumin.
Metabolism
Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase 2 enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose.
Excretion
Posaconazole is eliminated with a mean half-life (t1/2) of 35 hours (range 20 to 66 hours) and a total body clearance (CL/F) of 32 L/hr. Posaconazole is predominantly eliminated in the feces (71% of the radiolabeled dose up to 120 hours) with the major component eliminated as parent drug (66% of the radiolabeled dose). Renal clearance is a minor elimination pathway, with 13% of the radiolabeled dose excreted in urine up to 120 hours (<0.2% of the radiolabeled dose is parent drug).
Summary of Pharmacokinetic Parameters
The mean (%CV) [min–max] posaconazole average steady-state plasma concentrations (Cav) and steady-state pharmacokinetic parameters in patients following administration of 200 mg TID and 400 mg BID of the oral suspension are provided in TABLE 2.
TABLE 2. The Mean (%CV) [min–max] Posaconazole Steady-State Pharmacokinetic Parameters in Patients Following Oral Administration of Posaconazole 200 mg TID and 400 mg BID | DoseOral suspension administration | Cav (ng/mL) | AUCAUC (0–24 hr) for 200 mg TID and AUC (0–12 hr) for 400 mg BID
(ng∙hr/mL) | CL/F (L/hr) | V/F (L) | t1/2 (hr) |
|---|
| Note: Cav based on observed data; other pharmacokinetic parameters based on estimates from population pharmacokinetic analyses |
200 mg TIDAllogeneic hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease
(n=252) | 1103 (67)
[21.5–3650] | ND
| ND | ND | ND |
200 mg TIDNeutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes
(n=215) | 583 (65)
[89.7–2200] | 15,900 (62)
[4100–56,100] | 51.2 (54)
[10.7–146] | 2425 (39)
[828–5702] | 37.2 (39)
[19.1–148] |
400 mg BIDFebrile neutropenic patients or patients with refractory invasive fungal infections, Cav n=24
(n=23) | 723 (86)
[6.70–2256] | 9093 (80)
[1564–26,794] | 76.1 (78)
[14.9–256] | 3088 (84)
[407–13,140] | 31.7 (42)
[12.4–67.3] |
The variability in average plasma posaconazole concentrations in patients was relatively higher than that in healthy subjects.
Exposure Response Relationship
In clinical studies of immunocompromised patients, a wide range of plasma exposures to posaconazole was noted. A pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cav) and prophylactic efficacy. A lower Cav may be associated with an increased risk of treatment failure [defined in the study as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or invasive fungal infections (IFI)].
To enhance the oral absorption of posaconazole and optimize plasma concentrations:
- Each dose of NOXAFIL® Oral Suspension should be administered with a full meal or liquid nutritional supplement. For patients who can not eat a full meal or tolerate an oral nutritional supplement, alternative antifungal therapy should be considered or patients should be monitored closely for breakthrough fungal infections.
- Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections.
- Co-administration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections. (See CLINICAL PHARMACOLOGY, Drug Interactions.)
Pharmacokinetics in Special Populations
Gender
The pharmacokinetics of posaconazole are comparable in men and women. No adjustment in the dosage of NOXAFIL® is necessary based on gender.
Race
The pharmacokinetic profile of posaconazole is not significantly affected by race. No adjustment in the dosage of NOXAFIL® is necessary based on race.
Geriatric
The pharmacokinetics of posaconazole are comparable in young and elderly subjects (≥65 years of age). No adjustment in the dosage of NOXAFIL® is necessary in elderly patients (≥65 years of age) based on age.
Pediatric
In the prophylaxis studies, the mean steady-state posaconazole average concentration (Cav) was similar among ten adolescents (13–17 years of age) and adults (≥18 years of age). This is consistent with pharmacokinetic data from another study in which mean steady-state posaconazole Cav from 12 adolescent patients (8–17 years of age) was similar to that in the adults (≥18 years of age).
Hepatic Insufficiency
The pharmacokinetic data in subjects with hepatic impairment was not sufficient to determine if dose adjustment is necessary in patients with hepatic dysfunction. It is recommended that posaconazole be used with caution in patients with hepatic impairment. (See WARNINGS and DOSAGE AND ADMINISTRATION.)
Renal Insufficiency
Following single-dose administration of 400 mg of the oral suspension, there was no significant effect of mild (CLcr: 50–80 mL/min/1.73m2, n=6) and moderate (CLcr: 20–49 mL/min/1.73m2, n=6) renal insufficiency on posaconazole pharmacokinetics; therefore, no dose adjustment is required in patients with mild to moderate renal impairment. In subjects with severe renal insufficiency (CLcr: <20 mL/min/1.73m2), the mean plasma exposure (AUC) was similar to that in patients with normal renal function (CLcr: >80 mL/min/1.73m2); however, the range of the AUC estimates was highly variable (CV=96%) in these subjects with severe renal insufficiency as compared to that in the other renal impairment groups (CV<40%). Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections. (See DOSAGE AND ADMINISTRATION.)
Electrocardiogram Evaluation
Multiple, time-matched ECGs collected over a 12-hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers (18–85 years of age) administered posaconazole 400 mg BID with a high fat meal. In this pooled analysis, the mean QTc (Fridericia) interval change from baseline was -5 msec following administration of the recommended clinical dose. A decrease in the QTc(F) interval (-3 msec) was also observed in a small number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc(F) interval change from baseline was <0 msec (-8 msec). No healthy subject administered posaconazole had a QTc(F) interval ≥500 msec or an increase ≥60 msec in their QTc(F) interval from baseline. (See PRECAUTIONS.)
Drug Interactions
Effect of Other Drugs on Posaconazole
Posaconazole is primarily metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. A summary of drugs studied clinically, which affect posaconazole concentrations, is provided in TABLE 3. (See PRECAUTIONS, Drug Interactions).
TABLE 3. Summary of the Effect of Co-administered Drugs on Posaconazole in Healthy Volunteers | | | Effect on Bioavailability of Posaconazole | |
|---|
| Co-administered Drug (Postulated Mechanism of Interaction) | Co-administered Drug Dose/Schedule | Posaconazole Dose/Schedule | Change in Mean Cmax
(ratio estimate ; 90% Cl of the ratio estimate) | Change in Mean AUC
(ratio estimate; 90% Cl of the ratio estimate) | Recommendations |
|---|
Rifabutin
(UDP-G Induction) | 300 mg QD × 17 days | 200 mg (tablets)
QD × 10 days | ↓43%
(0.57; 0.43–0.75) | ↓49%
(0.51; 0.37–0.71) | Avoid concomitant use unless the benefit outweighs the risks. |
Phenytoin
(UDP-G Induction) | 200 mg QD × 10 days | 200 mg (tablets)
QD × 10 days | ↓41%
(0.59; 0.44–0.79) | ↓50%
(0.50; 0.36–0.71) | Avoid concomitant use unless the benefit outweighs the risks. |
Cimetidine
(Alteration of Gastric pH) | 400 mg BID × 10 days | 200 mg (tablets)
QD × 10 days | ↓39%
(0.61; 0.53–0.70) | ↓39%
(0.61; 0.54–0.69) | Avoid concomitant use unless the benefit outweighs the risks. |
Efavirenz
(UDP-G Induction) | 400 mg QD × 10 and 20 days | 400 mg (oral suspension) BID × 10 and 20 days | ↓45%
(0.55; 0.47–0.66) | ↓50%
(0.50; 0.43–0.60) | Avoid concomitant use unless the benefit outweighs the risks. |
Co-administration of these drugs listed in TABLE 3 with posaconazole may result in lower plasma concentrations of posaconazole.
No clinically relevant effect on posaconazole bioavailability and/or plasma concentrations was observed when administered with an antacid, glipizide, ritonavir, H2 receptor antagonists other than cimetidine, or proton pump inhibitors; therefore, no posaconazole dose adjustments are required when used concomitantly with these products.
Effect of Posaconazole on Other Drugs
In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4. A clinical study in healthy volunteers also indicates that posaconazole is a strong CYP3A4 inhibitor as evidenced by a >5-fold increase in midazolam AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. A summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in TABLE 4. (See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS, Drug Interactions.)
TABLE 4. Summary of the Effect of Posaconazole on Co-administered Drugs in Healthy Volunteers and Patients | | | Effect on Bioavailability of Co-administered Drugs | |
|---|
| Co-administered Drug (Postulated Mechanism of Interaction) | Co-administered Drug Dose/Schedule | Posaconazole Dose/Schedule | Change in Mean Cmax
(ratio estimate ; 90% Cl of the ratio estimate) | Change in Mean AUC
(ratio estimate; 90% Cl of the ratio estimate) | Recommendations |
|---|
Sirolimus
(Inhibition of CYP3A4 by posaconazole) | 2 mg single oral dose | 400 mg (oral suspension) BID × 16 days | ↑ 572%
(6.72; 5.62–8.03) | ↑ 788%
(8.88; 7.26–10.9 | Coadministration of posaconazole with sirolimus is contraindicated (see CONTRAINDICATIONS). |
Cyclosporine
(Inhibition of CYP3A4 by posaconazole) | Stable maintenance dose in heart transplant recipients | 200 mg (tablets)
QD × 10 days | ↑ cyclosporine whole blood trough concentrations
Cyclosporine dose reductions of up to 29% were required | At initiation of posaconazole treatment, reduce the cyclosporine dose to approximately three-fourths of the original dose.
Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly. |
Tacrolimus
(Inhibition of CYP3A4 by posaconazole) | 0.05 mg/kg single oral dose | 400 mg (oral suspension)
BID × 7 days | ↑ 121%
(2.21; 2.01–2.42) | ↑ 358%
(4.58; 4.03–5.19) | At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose.
Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly. |
Rifabutin
(Inhibition of CYP3A4 by posaconazole) | 300 mg QD × 17 days | 200 mg
(tablets)
QD × 10 days | ↑ 31%
(1.31; 1.10–1.57) | ↑ 72%
(1.72; 1.51–1.95) | Avoid concomitant use unless the benefit outweighs the risks. If the drugs are co-administered, frequent monitoring of rifabutin adverse effects (eg, uveitis, leukopenia) should be performed. |
Midazolam
(Inhibition of CYP3A4 by posaconazole) | Single 30 min IV infusion of 0.05 mg/kg | 200 mg
(tablets)
QD × 10 days | NANA: Not applicable if administered as an IV | ↑ 83%
(1.83;
1.57–2.14) | Frequent monitoring of adverse effects of benzodiazepines metabolized by CYP3A4 should be performed and dose reduction of these benzodiazepines should be considered during co-administration with posaconazole. |
| | | | | |
| 0.4 mg single IV dose
| 200 mg (oral suspension) BID × 7 days | ↑ 30%
(1.3; 1.13–1.48) | ↑ 362%
(4.62; 4.02–5.3) |
| | | | | |
| 2 mg single oral dose | 200 mg (oral suspension) BID × 7 days | ↑ 126%
(2.26; 2.02–2.53) | ↑ 362%
(4.59; 4.12–5.11) |
| | | | | |
| 0.4 mg single IV dose | 400 mg (oral suspension) BID × 7 days | ↑ 62%
(1.62; 1.41–1.86) | ↑ 524%
(6.24; 5.43–7.16) |
Phenytoin
(Inhibition of CYP3A4 by posaconazole) | 200 mg QD PO × 10 days | 200 mg
(tablets)
QD × 10 days | ↑ 16%
(1.16; 0.85–1.57) | ↑ 16%
(1.16; 0.84–1.59) | Frequent monitoring of phenytoin concentrations should be performed while co-administered with posaconazole and dose reduction of phenytoin should be considered. |
Ritonavir
(Inhibition of CYP3A4 by posaconazole) | 100 mg QD × 14 days | 400 mg (oral suspension) BID × 7 days | ↑ 49%
(1.49; 1.04–2.15) | ↑ 80%
(1.8; 1.39–2.31) | Frequent monitoring of adverse effects and toxicity of ritonavir should be performed during co-administration with posaconazole. |
Atazanavir
(Inhibition of CYP3A4 by posaconazole) | 300 mg QD × 14 days | 400 mg (oral suspension) BID × 7 days | ↑ 155%
(2.55; 1.89–3.45) | ↑ 268%
(3.68; 2.89–4.70) | Frequent monitoring of adverse effects and toxicity of Atazanavir should be performed during co-administration with posaconazole. |
| | | | | |
Atazanavir/ritonavir boosted regimen
(Inhibition of CYP3A4 by posaconazole) | 300 mg/100 mg QD × 14 days | 400 mg (oral suspension) BID × 7 days | ↑ 53%
(1.53; 1.13–2.07) | ↑ 146%
(2.46; 1.93–3.13) |
Additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, ritonavir, indinavir, or caffeine were observed when administered with posaconazole 200 mg QD; therefore, no dose adjustments are required for these co-administered drugs when co-administered with posaconazole 200 mg QD.
Posaconazole administration with glipizide does not require a dose adjustment in either drug; however, glucose concentrations decreased in some healthy volunteers administered the combination. Therefore, glucose concentrations should be monitored in accordance with the current standard of care for patients with diabetes when posaconazole is co-administered with glipizide.
|
