Population pharmacokinetics of molnupiravir in adults with COVID-19: Lack of clinically important exposure variation across individuals.

Effective antiviral treatments for coronavirus disease 2019 (COVID-19) are needed to reduce the morbidity and mortality associated with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, particularly in patients with risk factors for severe disease. Molnupiravir (MK-4482, EIDD-2801) is an orally administered, ribonucleoside prodrug of ß-D-N4-hydroxycytidine (NHC) with submicromolar potency against SARS-CoV-2. A population pharmacokinetic (PopPK) analysis for molnupiravir exposure was conducted using 4202 NHC plasma concentrations collected in 1207 individuals from a phase I trial in healthy participants, a phase IIa trial in non-hospitalized participants with COVID-19, a phase II trial in hospitalized participants with COVID-19, and a phase II/III trial in non-hospitalized participants with COVID-19. Molnupiravir pharmacokinetics (PK) was best described by a two-compartment model with a transit-compartment absorption model and linear elimination. Molnupiravir apparent elimination clearance increased with body weight less-than-proportionally (power 0.412) and was estimated as 70.6 L/h in 80-kg individuals with a moderate interindividual variability (43.4% coefficient of variation). Additionally, effects of sex and body mass index on apparent central volume and food status and formulation on the absorption mean transit time were identified as statistically significant descriptors of variability in these PK parameters. However, none of the identified covariate effects caused clinically relevant changes in the area under the NHC concentration versus time curve between doses, the exposure metric most closely related to clinical response. Overall, the PopPK model indicates that molnupiravir can be administered in adults without dose adjustment based on age, sex, body size, food, and mild-to-moderate renal or mild hepatic impairment.

Phase 1b/3 Pharmacokinetics and Safety Study of Intravenous Posaconazole in Adult Asian Participants at High Risk for Invasive Fungal Infections.

INTRODUCTION: Antifungal prophylaxis in patients at high risk for invasive fungal infections (IFIs), such as those with acute myeloid leukemia or myelodysplastic syndromes, continues to be underused in Asia, despite the fact that it reduces IFI-related death and increases IFI-free survival. We characterized the pharmacokinetics (PK) and safety of the intravenous (IV) formulation of posaconazole in adult Asian participants at high risk for IFI. METHODS: Participants received posaconazole IV 300 mg twice on day 1, posaconazole IV 300 mg once daily on days 2-10, and posaconazole IV 300 mg once daily or oral suspension 200 mg 3 times daily for up to 18 days for a maximum of 28 days. There were two PK sampling groups: intensive and sparse. Sparse trough PK sampling was collected from all participants on days 3, 6, 10, 15, 22, and 28/end of treatment. The intensive PK group had additional sampling performed over 24 h on day 10. Primary end points were steady state average concentration (Cavg,ss) and percentage of participants with Cavg,ss ≥ 500 ng/mL. Safety was assessed up to day 30/end of treatment. RESULTS: Seventy participants with acute myelogenous leukemia were enrolled, 30 in the intensive PK group and 40 in the sparse PK group; 57 participants completed the study, 26 in the intensive PK group and 31 in the sparse PK group. On day 10, arithmetic mean Cavg,ss was 2986 ng/mL [coefficient of variation (%CV), 36%; range, 1409-5930 ng/mL]; 100% of participants in the intensive PK group (n/N = 27/27) had Cavg,ss ≥ 500 ng/mL. Arithmetic mean (%CV) Cmin was 2474 (50.4%) and 2466 ng/mL (42.4%) in the intensive and sparse PK groups on day 10, respectively. Safety was similar to that of previous posaconazole formulations. CONCLUSION: In Asian participants at high risk for IFIs, IV posaconazole achieved the target exposure associated with efficacy that was previously established for supporting global registration of posaconazole for IV administration and was generally well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03336502.

A phase 1 pooled PK/PD analysis of bone resorption biomarkers for odanacatib, a Cathepsin K inhibitor.

To develop a framework for evaluating the resorption effects of Cathepsin K (CatK) inhibitors and to inform dose regimen selection, a pharmacokinetic/pharmacodynamic (PK/PD) model for odanacatib (ODN) was developed based upon data from Phase 1 studies. Pooled PK/PD data from 11 studies (N = 249) were fit reasonably to a population inhibitory sigmoid Emax model. Body weight on E0 (baseline uNTx/Cr, urinary N-terminal telopeptide normalized by creatinine) and age on Emax (fractional inhibition of the biomarker response) were significant covariates for biomarker response. Simulations of typical osteoporosis patients (by age, sex and weight) indicated minimal differences between sexes in concentration-uNTx/Cr relationship. There was no evidence that regimen (daily vs. weekly dosing) influenced the PK/PD relationship of resorption inhibition for odanacatib. PK/PD models based on data from odanacatib (ODN) Phase 1 studies demonstrated that uNTx/Cr was an appropriate bone resorption biomarker for assessment of the effects of a CatK inhibitor. The models also identified the determinants of response in the PK/PD relationship for ODN (body weight on E0 and age on Emax).

Assessment of Drug Interaction Potential Between the Hepatitis C Virus Direct-Acting Antiviral Agents Elbasvir/Grazoprevir and the Nucleotide Analog Reverse-Transcriptase Inhibitor Tenofovir Disoproxil Fumarate.

Treatment of individuals coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) requires careful consideration of potential drug-drug interactions. We evaluated the pharmacokinetic interaction of the direct-acting antiviral agents elbasvir and grazoprevir coadministered with the nucleotide reverse transcriptase inhibitor tenofovir disoproxil fumarate (TDF). Three open-label, multidose studies in healthy adults were conducted. In the first study (N = 10), participants received TDF 300 mg once daily, elbasvir 50 mg once daily, and elbasvir coadministered with TDF. In the second study (N = 12), participants received TDF 300 mg once daily, grazoprevir 200 mg once daily, and grazoprevir coadministered with TDF. In the third study (N = 14), participants received TDF 300 mg once daily and TDF 300 mg coadministered with coformulated elbasvir/grazoprevir 50 mg/100 mg once daily. Pharmacokinetics and safety were evaluated. Following coadministration, the tenofovir area under the plasma concentration-time curve to 24 hours and maximum plasma concentration geometric mean ratios (90% confidence intervals) for tenofovir and coadministered drug(s) versus tenofovir were 1.3 (1.2, 1.5) and 1.5 (1.3, 1.6), respectively, when coadministered with elbasvir; 1.2 (1.1, 1.3) and 1.1 (1.0, 1.2), respectively, when coadministered with grazoprevir; and 1.3 (1.2, 1.4) and 1.1 (1.0, 1.4), respectively, when coadministered with the elbasvir/grazoprevir coformulation. TDF had minimal effect on elbasvir and grazoprevir pharmacokinetics. Elbasvir and/or grazoprevir coadministered with TDF resulted in no clinically meaningful tenofovir exposure increases and was generally well tolerated, with no deaths, serious adverse events (AEs), discontinuations due to AEs, or laboratory AEs reported. No dose adjustments for elbasvir/grazoprevir or TDF are needed for coadministration in HCV/HIV-coinfected people.

Pharmacokinetic Interactions Between the Fixed-Dose Combinations of Elvitegravir/Cobicistat/Tenofovir Disoproxil Fumarate/Emtricitabine and Elbasvir/Grazoprevir in Healthy Adult Participants.

Treatment of individuals coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) requires careful consideration of potential drug-drug interactions. The pharmacokinetic interaction of the HCV fixed-dose combination treatment of elbasvir/grazoprevir (EBR/GZR) when coadministered with the fixed-dose combination HIV treatment of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine (EVG/COB/TDF/FTC) was evaluated in 22 healthy adults. In period 1, oral doses of EVG/COB/TDF/FTC (150 mg/150 mg/300 mg/200 mg) were administered once daily for 7 days. In period 2, oral doses of EBR/GZR (50 mg/100 mg) were administered once daily for 10 days. In period 3, oral doses of EVG/COB/TDF/FTC were coadministered with EBR/GZR once daily for 10 days. The pharmacokinetics of EVG/COB/TDF/FTC were not clinically meaningfully altered by concomitant EBR/GZR administration. Geometric mean ratios (90%CIs) for area under the plasma concentration-time curve from time 0 to 24 hours (AUC0-24 ) in the presence/absence of EBR/GZR were 1.1 (1.0, 1.2) for elvitegravir; 1.1 (1.0, 1.1) for emtricitabine; 1.2 (1.1, 1.2) for tenofovir; and 1.5 (1.4, 1.6) for cobicistat. In comparison, the AUC0-24 of elbasvir was ∼2 times higher and the AUC0-24 of grazoprevir was ∼5 times higher following concomitant administration of EVG/COB/TDF/FTC and EBR/GZR. Geometric mean ratios (90%CI) for AUC0-24 in the presence/absence of EVG/COB/TDF/FTC were 2.2 (2.0, 2.4) for elbasvir and 5.4 (4.5, 6.4) for grazoprevir. Coadministration of EVG/COB/TDF/FTC and EBR/GZR was generally well tolerated in healthy adults in this study. Nevertheless, because of the increased GZR exposure that occurs with coadministration of EVG/COB/TDF/FTC and EBR/GZR, coadministration of this combination is not recommended in those coinfected with HIV and HCV.

Pharmacokinetic Interactions between the Hepatitis C Virus Inhibitors Elbasvir and Grazoprevir and HIV Protease Inhibitors Ritonavir, Atazanavir, Lopinavir, and Darunavir in Healthy Volunteers.

The combination of the hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor elbasvir and the NS3/4A protease inhibitor grazoprevir is a potent, once-daily therapy indicated for the treatment of chronic HCV infection in individuals coinfected with human immunodeficiency virus (HIV). We explored the pharmacokinetic interactions of elbasvir and grazoprevir with ritonavir and ritonavir-boosted HIV protease inhibitors in three phase 1 trials. Drug-drug interaction trials with healthy participants were conducted to evaluate the effect of ritonavir on the pharmacokinetics of grazoprevir (n = 10) and the potential two-way pharmacokinetic interactions of elbasvir (n = 30) or grazoprevir (n = 39) when coadministered with ritonavir-boosted atazanavir, lopinavir, or darunavir. Coadministration of ritonavir with grazoprevir increased grazoprevir exposure; the geometric mean ratio (GMR) for grazoprevir plus ritonavir versus grazoprevir alone area under the concentration-time curve from 0 to 24 h (AUC0-24) was 1.91 (90% confidence interval [CI]; 1.31 to 2.79). Grazoprevir exposure was markedly increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for grazoprevir AUC0-24 of 10.58 (90% CI, 7.78 to 14.39), 12.86 (90% CI, 10.25 to 16.13), and 7.50 (90% CI, 5.92 to 9.51), respectively. Elbasvir exposure was increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for elbasvir AUC0-24 of 4.76 (90% CI, 4.07 to 5.56), 3.71 (90% CI, 3.05 to 4.53), and 1.66 (90% CI, 1.35 to 2.05), respectively. Grazoprevir and elbasvir had little effect on atazanavir, lopinavir, and darunavir pharmacokinetics. Coadministration of elbasvir-grazoprevir with atazanavir-ritonavir, lopinavir-ritonavir, or darunavir-ritonavir is contraindicated, owing to an increase in grazoprevir exposure. Therefore, HIV treatment regimens without HIV protease inhibitors should be considered for HCV/HIV-coinfected individuals who are being treated with elbasvir-grazoprevir.

No Pharmacokinetic Interactions Between Elbasvir or Grazoprevir and Buprenorphine/Naloxone in Healthy Participants and Participants Receiving Stable Opioid Agonist Therapy.

The aims of these phase I trials were to evaluate the pharmacokinetic interaction between elbasvir (EBR) or grazoprevir (GZR) and buprenorphine/naloxone (BUP/NAL). Trial 1 was a single-dose trial in healthy participants. Trial 2 was a multiple-dose trial in participants on BUP/NAL maintenance therapy. Coadministration of EBR or GZR with BUP/NAL had minimal effect on the pharmacokinetics of BUP/NAL, EBR, and GZR. The geometric mean ratios (GMRs (90% CI)) for BUP, norbuprenorphine, and NAL AUC0-∞ were 0.98 (0.89-1.08), 0.97 (0.86-1.09), and 0.88 (0.78-1.00) in the presence/absence of EBR; 0.98 (0.81-1.19), 1.13 (0.97-1.32), and 1.10 (0.82-1.47) in the presence/absence of GZR. The GMRs (90% CI) for EBR and GZR AUC0-∞ in the absence/presence of BUP/NAL were 1.22 (0.98-1.52) and 0.86 (0.63-1.18). In conclusion, no dose adjustment for BUP/NAL, EBR, or GZR is required for patients with HCV infection receiving EBR/GZR and BUP/NAL maintenance therapy.

No Pharmacokinetic Interactions Between Elbasvir or Grazoprevir and Methadone in Participants Receiving Maintenance Opioid Agonist Therapy.

We conducted two phase I trials to evaluate the pharmacokinetic interactions between elbasvir (EBR), grazoprevir (GZR), and methadone (MK-8742-P010 and MK-5172-P030) in non-hepatitis C virus (HCV)-infected participants on methadone maintenance therapy. Coadministration of EBR or GZR with methadone had no clinically meaningful effect on EBR, GZR, or methadone pharmacokinetics. The geometric mean ratios (GMRs) for R- and S-methadone AUC0-24 were 1.03 (90% confidence interval (CI), 0.92-1.15) and 1.09 (90% CI, 0.94-1.26) in the presence/absence of EBR; and 1.09 (90% CI, 1.02-1.17) and 1.23 (90% CI, 1.12-1.35) in the presence/absence of GZR. The GMRs for EBR and GZR AUC0-24 in participants receiving methadone relative to a healthy historical cohort not receiving methadone were 1.20 (90% CI, 0.94-1.53) and 1.03 (90% CI, 0.76-1.41), respectively. These results indicate that no dose adjustment is required for individuals with HCV infection receiving stable methadone therapy and the EBR/GZR fixed-dose regimen.

Effect of tildrakizumab (MK-3222), a high affinity, selective anti-IL23p19 monoclonal antibody, on cytochrome P450 metabolism in subjects with moderate to severe psoriasis.

AIMS: Tildrakizumab, an interleukin (IL)-23 inhibitor, is indicated for the treatment of moderate to severe chronic plaque psoriasis. Although tildrakizumab is not metabolized by, and does not alter, cytochrome P450 (CYP) expression in vitro, clinically significant pharmacokinetic effects through changes in systemic inflammation, which alters CYP metabolism, have been well documented. At the time of study conduct, the effect of modulation of inflammation/cytokines, including IL-23 inhibition with tildrakizumab, on CYP metabolism, and therefore the potential for disease-drug interactions, in psoriasis patients was unknown. We therefore assessed whether tildrakizumab alters CYP metabolism in subjects with moderate to severe psoriasis. METHODS: This was an open-label, fixed-sequence, two-period trial. In Period 1 (Day 1), subjects received an oral CYP probe cocktail of up to five drugs (midazolam 2 mg [3A4], caffeine 200 mg [1A2], warfarin 10 mg [2C9], omeprazole 40 mg [2C19] and dextromethorphan 30 mg [2D6]), followed by a 7-day washout. In Period 2, subjects received tildrakizumab 200 mg subcutaneously on Days 1 and 29 and a second CYP probe cocktail on Day 57. Substrate or metabolite pharmacokinetics, safety and changes in Psoriasis Severity Area Index (PASI), interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP), were assessed. RESULTS: Twenty subjects (13 men, 7 women) were enrolled. Tildrakizumab had no clinically relevant effect on the pharmacokinetics of any of the probe substrates tested. On Day 57 of Period 2, the median percentage decrease from baseline in PASI score following tildrakizumab was ~93%. There were no clinically relevant changes in IL-6 or hs-CRP. Treatment with tildrakizumab was generally well tolerated. CONCLUSION: In subjects with moderate to severe psoriasis, tildrakizumab 200 mg did not have a discernible effect on CYP metabolism. The potential for clinically significant drug-drug interactions (DDIs) with tildrakizumab in patients with psoriasis is low. The difference in the occurrence of DDIs seen with anti-inflammatory agents in rheumatoid arthritis patients compared with psoriasis patients may be due to the much greater extent of systemic inflammation in rheumatoid arthritis as compared to psoriasis.

The Absence of a Clinically Significant Effect of Food on the Single Dose Pharmacokinetics of Vorapaxar, a PAR-1 Antagonist, in Healthy Adult Subjects.

In this open-label, randomized, 2-period crossover study, 16 healthy subjects received a single oral 2.5-mg dose of vorapaxar in the fed (i.e., standardized high-fat breakfast) and fasted (i.e., an overnight fast) state with a 6-week washout. Plasma samples for vorapaxar assay were obtained pre-dose and up to 72 hours post-dose. Least squares (LS) geometric mean AUC0-72 hr and Cmax were analyzed by ANOVA. If 90% confidence intervals (CI) for the geometric mean ratios (GMRs; fed/fasted) of AUC0-72 hr and Cmax were within the 50-200% range, then food was deemed not to have a clinically important effect. The LS geometric mean (90% CI) AUC0-72 hr and Cmax of vorapaxar in the fasted state were 314 (284-348) ng hr/mL and 23.4 (20.7-26.4) ng/mL, respectively. The GMRs (fed/fasted) and 90% CIs for AUC0-72 hr and Cmax were 96.9 (92.2-102) and 79.1 (67.6-92.5), respectively. Vorapaxar was generally safe and well tolerated in the presence and absence of food. Concomitant food decreased the rate (i.e., 21% reduction in Cmax and 45-min delay in Tmax ) with no effect on the extent of vorapaxar absorption when administered as a single 2.5-mg dose. Thus, vorapaxar can be administered without regard to food.

Single-dose phase I study to evaluate the pharmacokinetics of posaconazole in new tablet and capsule formulations relative to oral suspension.

Posaconazole oral suspension, a marketed extended-spectrum triazole with proven efficacy as antifungal treatment and prophylaxis, should be taken with food to maximize absorption. New tablet and capsule formulations have been developed in an attempt to optimize absorption and bioavailability. The aims of this exploratory open-label, partially randomized, 2-part, 4-way, single-dose crossover study in 16 healthy adults were to characterize pharmacokinetics for posaconazole tablet and capsule formulations relative to those for posaconazole oral suspension under fasted and fed conditions and to assess safety and tolerability. Under fasted conditions, posaconazole exposures (area under the curve [AUC]) for the tablet and capsule formulations were similar (mean AUC from time zero to infinity [AUC(0-∞)], tablet A, 11,700 ng · h/ml [coefficient of variation {CV}, 26%]; tablet B, 11,300 ng · h/ml [CV, 22%]; capsule, 11,000 ng · h/ml [CV, 25%]) and were substantially higher than the exposure for the oral suspension (mean AUC(0-∞), 3,420 ng · h/ml [CV, 44%]). Tablets and capsule showed less variability in exposure than the oral suspension. In fed subjects, tablets and capsule resulted in similar AUC values (mean AUC(0-∞), tablet A, 11,900 ng · h/ml [23%]; tablet B, 12,400 ng · h/ml [CV, 25%]; capsule, 12,300 ng · h/ml [CV, 28%]) and slightly higher exposure than the oral suspension (mean AUC(0-∞), 8,750 [CV, 24%]). Median times to the maximum concentration of drug in plasma were 4 to 5 h (fasted conditions) and 6 to 8 h (fed conditions). Mean half-lives values were similar for all formulations under fed and fasted conditions (23.1 to 29.2 h). Consistent with previous data, exposure for the oral suspension increased 2.5- to 3-fold when it was given with a high-fat meal. Conversely, exposures for tablets and capsule were not markedly affected by food. All formulations of posaconazole at 100 mg were safe and well tolerated.

Vorapaxar, an oral PAR-1 receptor antagonist, does not affect the pharmacokinetics and pharmacodynamics of warfarin.

PURPOSE: Vorapaxar is an orally active protease-activated receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet aggregation. This open-label study assessed the pharmacokinetics and pharmacodynamics of single-dose warfarin in the presence/absence of multiple-dose vorapaxar in 12 healthy men. METHODS: Subjects received two treatments separated by ≥ 7-day washout: Treatment A warfarin 25 mg (Day 1); Treatment B vorapaxar 2.5 mg/day on Days 1-6 and vorapaxar 40 mg coadministered with warfarin 25 mg (Day 7). R-warfarin, S-warfarin, and prothrombin time (PT) were assayed predose and up to 120 h postdose. RESULTS: The geometric mean ratio (GMR) as a percentage (warfarin + vorapaxar/warfarin) was calculated. The GMR (90 % CIs) estimates of C(max) were 105 (99, 111) and 105 (99, 112) for R- and S-warfarin, respectively. The GMR (90 % CIs) estimates of AUC(0-∞) were 108 (101, 116) and 105 (96, 115) for R- and S-warfarin, respectively. The GMR (95 % CIs) estimates of AUC(0-120 h) for PT and INR were 97 (95, 98) and 96 (94, 98), respectively. CONCLUSION: Results of this study indicate that vorapaxar has no meaningful effect on the pharmacokinetics or pharmacodynamics of warfarin, suggesting that the coadministration of these two drugs or vorapaxar coadministered with other CYP2C9/CYP2C19 substrates is unlikely to cause a clinically significant pharmacokinetic drug interaction.

Effect of posaconazole on the pharmacokinetics of simvastatin and midazolam in healthy volunteers.

OBJECTIVES: The aim of the study is to determine the effect of posaconazole , an extended-spectrum triazole, on the pharmacokinetics of the HMG-CoA reductase inhibitor, simvastatin. METHODS: This randomized, fixed-sequence, parallel-group, single-center, open-label study was conducted in 35 healthy volunteers randomly assigned to receive one of three doses of oral posaconazole: 50, 100 or 200 mg. All subjects received single doses of the reference drug midazolam (2 mg oral) alone on day -9; simvastatin (40 mg oral) alone on day -6; posaconazole (50, 100 or 200 mg) on days 1 - 7 once daily (q.d.); posaconazole plus midazolam (day 8); posaconazole alone (days 9 - 10); posaconazole plus simvastatin (day 11) and posaconazole alone (days 12 - 13). RESULTS: Relative to simvastatin alone, posaconazole (50, 100 and 200 mg q.d.) significantly increased the C(max) and AUC of simvastatin (5- to 11-fold increase in AUC) and simvastatin acid (5- to 8-fold increase in AUC) during co-administration. Relative to midazolam alone, posaconazole (50, 100 and 200 mg q.d.) significantly inhibited CYP3A4-mediated metabolism of midazolam (three to sixfold increase in AUC). CONCLUSION: These findings support the classification of posaconazole as a strong CYP3A4 inhibitor. Simvastatin, or other statins predominantly metabolized by CYP3A4, should not be co-administered with posaconazole. Other statins, whose metabolism/elimination is not affected by CYP3A4 inhibition, should be considered for co-administration.

Determination of posaconazole levels in toenails of adults with onychomycosis following oral treatment with four regimens of posaconazole for 12 or 24 weeks.

Pharmacokinetic data from a randomized, parallel-group, multicenter study are presented. Adults with toenail onychomycosis (n = 146) received posaconazole (100 mg, 200 mg, or 400 mg) once daily (QD) for 24 weeks or 400 mg QD for 12 weeks. The posaconazole concentration in the great toenail exhibited a dose-related increase starting at week 2 for 24 weeks and a mean toenail-to-plasma concentration ratio of approximately 3:1 at the end of treatment for the 400-mg 24-week dose.

Skin concentrations and pharmacokinetics of posaconazole after oral administration.

A randomized, single-center, open-label study of posaconazole (POS) was performed to determine the concentration of POS in the skin of 30 healthy adult human subjects receiving 400 mg POS oral suspension twice daily for 8 days with a high-fat meal. Blood samples for plasma POS level determination were collected at prespecified times on day 1 and day 8. From each subject, two 4-mm skin punch biopsy samples were obtained, one immediately before or after both the first and last doses of POS. A MIC(90) value of 250 ng/ml, which encompasses the majority of common dermatophytes, was used to calculate the time above the MIC(90) in plasma and skin. On days 1 and 8, POS attained peak plasma concentrations at median times of 8 and 5 h, respectively. On days 1 and 8, POS peak skin concentrations were attained at 12 and 3 h, respectively; peak skin concentrations were produced from a single composite profile. On day 8, POS concentrations in skin and plasma for the entire dosing interval were severalfold higher than the MIC(90). POS dosed at 400 mg twice daily per os was well tolerated in healthy subjects. Two subjects reported increased alanine aminotransferase (ALT) levels. The findings of this study demonstrate adequate skin penetration and have certain implications for the treatment of dermatophytic skin and nail infections.

Effects of oral posaconazole on the pharmacokinetic properties of oral and intravenous midazolam: a phase I, randomized, open-label, crossover study in healthy volunteers.

BACKGROUND: Like itraconazole and ketoconazole, posaconazole, a broad-spectrum oral triazole antifungal, inhibits the activity of the cytochrome P450 (CYP) isozyme 3A4. Midazolam, a short-acting benzodiazepine, is metabolized by CYP3A4. Potential drug interactions can be expected in patients who are concurrently receiving inhibitors and substrates of CYP3A4 (eg, ketoconazole, posaconazole) and benzodiazepines (eg, midazolam). Because of the potential for drug interactions, it is important to determine the effects of posaconazole on the pharmacokinetic properties of midazolam. OBJECTIVE: The aim of this study was to compare the effects of oral administration of posaconazole versus ketoconazole on the pharmacokinetic properties of orally and intravenously administered midazolam. METHODS: This Phase I, randomized, open-label, crossover study was conducted at Swiss Pharma Contract Ltd., Allschwil, Switzerland. Healthy volunteers were randomly assigned to 1 of 2 treatment arms. Arm 1 received posaconazole 200 mg BID for 7 days, posaconazole 400 mg BID for 7 days, no drugs during a 28-day washout, and ketoconazole 400 mg once daily for 7 days. Arm 2 received posaconazole and ketoconazole in the reverse order, with a 28-day washout between treatments. An oral/IV midazolam sequence (oral midazolam 2 mg and IV midazolam 0.4 mg) was administered on days -2/-1, 6/7, 13/14 (arm 1), 36/17 (arm 2), 43/44, and 50/51 in both treatment arms. Blood samples were collected up to 24 hours after midazolam administration. Pharmacokinetic parameters, including C(max), C(min) (before azole administration), terminal-phase t(1/2) (t(1/2z)), and AUC to final measurable sampling time (AUC(tf)), were calculated using noncompartmental methods, and drug interactions were evaluated using analysis of variance. Adverse events were collected using physical examination, including vital sign measurements; clinical laboratory analysis; electrocardiography; and direct questioning at predefined time points throughout the study to assess tolerability. RESULTS: A total of 12 subjects were enrolled (11 men, 1 woman; all white; mean age, 42.8 years [range, 28-53 years]; mean weight, 80.6 kg; and mean body mass index, 25.6 kg/m(2)). All of the subjects completed the study. Based on point estimates of logarithm-transformed data, posaconazole 200 and 400 mg BID were associated with significant increases in midazolam C(max) (up to 1.3- and 2.4-fold) and AUC(tf) values (up to 4.6- and 6.2-fold), respectively. Ketoconazole 400 mg once daily was associated with significantly increased midazolam C(max) and AUC(tf) (up to 2.8- and 8.2-fold, respectively). When midazolam was concurrently administered with either azole, t(1/2z) was prolonged. Seven of 12 (58%) subjects reported > or =1 adverse event during the study (5 with posaconazole alone and 4 with posaconazole + midazolam). The most common adverse events were diarrhea (3 subjects [25%] with posaconazole alone, 2 [17%] with ketoconazole alone, and 1 [8%] with posaconazole + midazolam) and flatulence (1 [8%] with posaconazole alone and 1 [8%] with midazolam alone). CONCLUSIONS: The results from this study in a small, all-white population of healthy volunteers suggest that posaconazole was a potent inhibitor of CYP3A4, but to a lesser extent than was ketoconazole. Monitoring patients for adverse events, the need for dose adjustments, or both during coadministration with posaconazole may be warranted in patients being treated with benzodiazepines that are predominantly metabolized through CYP3A4 (eg, midazolam).

Effects of oral posaconazole on the pharmacokinetics of sirolimus.

OBJECTIVES: Azole antifungal agents are often coadministered with immunosuppressants to recipients of solid organ and hematopoietic stem cell transplants. Posaconazole, an extended-spectrum triazole, is an inhibitor of the cytochrome P450 (CYP) isoenzyme CYP3A4, and sirolimus, an immunosuppressant, is a substrate of the enzyme. We evaluated the effects of posaconazole on sirolimus pharmacokinetics in an open-label, multiperiod, drug-interaction study. METHODS: Twelve healthy subjects received one dose of sirolimus 2 mg on day 1. After a 28-day washout period, subjects received posaconazole 400 mg bid for 16 days (to day 45). On day 36, sirolimus 2 mg and posaconazole 400 mg were coadministered. Blood samples to determine sirolimus plasma concentrations were collected up to 216 hours post dose on days 1 and 36 and plasma pharmacokinetic parameters were calculated. Drug interactions were evaluated using one-way analysis of variance. Mean (% coefficient of variation) maximum plasma concentration (C(max)) and area under the curve (AUC) of sirolimus at day 1 were 4.9 ng/mL (38) and 145 h x ng/mL (45), respectively. RESULTS: Coadministration with posaconazole increased sirolimus C(max) and AUC by 6.7- and 8.9-fold, respectively. These increases are consistent with CYP3A4 inhibition by posaconazole. Adverse events were reported by five subjects (42%) receiving posaconazole and sirolimus and by three (25%) and eight (67%) subjects receiving posaconazole only on days 30 to 35 (presirolimus) and days 37 to 45 (postsirolimus), respectively. CONCLUSION: Because posaconazole has a clinically relevant effect on sirolimus exposure, the agents should probably not be coadministered. Although this was a descriptive study, one potential limitation was the small sample size. The conclusion could have been made stronger if the number of people enrolled in the study had been greater.

Pharmacokinetics of oral posaconazole in neutropenic patients receiving chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome.

STUDY OBJECTIVE: To analyze the pharmacokinetics of posaconazole administered as prophylaxis for invasive fungal infection (IFI) in neutropenic patients receiving chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). DESIGN: Pharmacokinetic subanalysis of a phase III, prospective, randomized, multicenter, evaluator-blinded trial comparing posaconazole with standard azoles (fluconazole and itraconazole). PATIENTS: One hundred ninety-four patients with AML or MDS who received posaconazole oral suspension 200 mg 3 times/day with meals or a nutritional supplement for a minimum of 7 days to achieve steady state and for a maximum of 12 weeks. INTERVENTION: For the first 20 patients, blood samples were collected before the first dose on day 8 and at 2, 4, 6, and 24 hours after that first dose; for all other patients, blood samples were collected at 1 and 3 hours after the first dose on day 8 and during the first episode of evaluation for a possible IFI. MEASUREMENTS AND MAIN RESULTS: The effects of the following covariates on average (Cav) and maximum (Cmax) posaconazole plasma concentrations at steady state were explored: age, sex, and race-ethnicity; proven or probable IFI; baseline body weight and body surface area; and baseline (on or before day 7) increases in liver enzyme levels, mucositis, neutropenia, diarrhea, vomiting, or use of an H2-receptor antagonist or proton pump inhibitor. Diarrhea, proton pump inhibitor use, gamma-glutamyl transferase level of 2 or more times the upper limit of normal, and race-ethnicity reduced Cav. Although statistically significant, these results were not considered clinically significant and did not necessitate posaconazole dosage adjustments. Mean Cav and Cmax values did not appear different in the six patients with IFIs (three with proven IFIs, three with probable IFIs) compared with the entire sample of 194 patients; however, a definitive conclusion cannot be made due to the small sample size of patients with IFI. No factor found to affect posaconazole concentrations predominated in patients with IFIs. CONCLUSION: Oral posaconazole 200 mg 3 times/day provided plasma concentrations adequate for preventing IFIs. No dosage adjustments are recommended based on any covariate tested.

Pharmacokinetics of oral posaconazole in allogeneic hematopoietic stem cell transplant recipients with graft-versus-host disease.

STUDY OBJECTIVE: To analyze the pharmacokinetics of posaconazole administered as prophylaxis for invasive fungal infections in recipients of hematopoietic stem cell transplants (HSCTs) who have graft-versus-host disease (GVHD). DESIGN: Pharmacokinetic analysis in a subset of posaconazole-treated patients from a large, multicenter, phase III, randomized, double-blind, double-dummy, parallel-group trial that compared posaconazole with fluconazole. SETTING: Ninety international medical centers. PATIENTS: The subset of patients comprised 246 HSCT recipients for whom pharmacokinetic data were available. INTERVENTION: All patients received posaconazole 200 mg oral suspension 3 times/day for a maximum of 16 weeks. MEASUREMENTS AND MAIN RESULTS: Blood samples were collected after dosing on day 2; at weeks 2, 4, 8, and 12; and on the last day of oral treatment. After patients had received posaconazole for at least 7 days (i.e., after achieving steady state), both maximum observed posaconazole concentration (C(max)) and average posaconazole concentration (C(av)) were determined. Five patients developed invasive fungal infections while receiving treatment. Median C(av) and C(max) were 611 and 635 ng/ml, respectively, in these five patients and were 922 and 1360 ng/ml, respectively, in the 241 patients without invasive fungal infection. In patients without invasive fungal infection, posaconazole concentrations were not clinically affected by race, body weight, or age. Median plasma posaconazole concentrations were higher in patients with chronic GVHD than in those with acute GVHD. In 18 patients without invasive fungal infection who experienced diarrhea on the day of sampling, posaconazole concentrations were lower than the concentrations in patients without diarrhea. No relationship was observed between alanine aminotransferase, aspartate aminotransferase, or bilirubin levels and posaconazole concentrations. CONCLUSION: Posaconazole 200 mg 3 times/day resulted in median plasma drug concentrations sufficiently high to prevent invasive fungal infections in HSCT recipients with GVHD, without compromising patient safety. Plasma posaconazole concentrations are generally unaffected by demographic variables, including race, sex, body weight, and age.

Effect of oral posaconazole on the pharmacokinetics of cyclosporine and tacrolimus.

STUDY OBJECTIVE: To analyze the pharmacokinetic properties of the immunosuppressants cyclosporine and tacrolimus when either is coadministered with oral posaconazole. DESIGN: Two single-center, open-label pharmacokinetic studies of cyclosporine in a multiple-dose design and of tacrolimus in a one-sequence, crossover, single- and multiple-dose design. SETTING: One clinical investigative center in the United States and one in the United Kingdom. SUBJECTS: Four adult heart transplant recipients in the cyclosporine study and 36 healthy adult volunteers in the tacrolimus study. INTERVENTIONS: In the cyclosporine study, patients who took an established cyclosporine dose 3 times/day for 6 weeks or longer were given posaconazole 200 mg/day for 10 days. In the tacrolimus study, subjects received tacrolimus 0.05 mg/kg/day on days 1 and 14 and posaconazole 400 mg twice/day on days 7-14. MEASUREMENTS AND MAIN RESULTS: In the cyclosporine study, blood samples were collected on day 1 to determine cyclosporine pharmacokinetics and on day 10 to measure the pharmacokinetics of cyclosporine and posaconazole. Coadministration of posaconazole increased cyclosporine exposure and necessitated dosage reductions of 14-29% for cyclosporine in three subjects. In the tacrolimus study, blood samples were collected on days 12-14 to assess posaconazole pharmacokinetics and on days 1 and 14 for as long 72 hours after dosing to evaluate tacrolimus pharmacokinetics. Posaconazole increased the maximum blood concentration and the area under the concentration-time curve for tacrolimus by 121% and 358%, respectively, on day 14 compared with day 1 (both p=0.001). In both studies, posaconazole pharmacokinetics were unaffected. CONCLUSION: These findings suggest that the dosage of cyclosporine or tacrolimus should be reduced when posaconazole therapy is started and that plasma levels of the immunosuppressant should be monitored during and at the discontinuation of posaconazole therapy so that dosages are adjusted accordingly. This recommendation is consistent with current standard of care for patients receiving cyclosporine or tacrolimus with concomitant azole antifungal therapy.