Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Posaconazole · 18 trials · 12 indications
An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol specified procedure, whether or not considered related to the medicinal product or protocol specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the Sponsor's product is also an AE.
The percentage of participants who died with posaconazole (POS) compared to voriconazole (VOR) in the first line treatment of invasive aspergillosis (IA) in the Intention to Treat (ITT) population through Day 42 was assessed.
Number of participants developing a proven or probable IFI from randomization to the last dosage date (up to 12 weeks \[84 days\]) plus 7 days. IFI diagnosis criteria may include: persistent fever, failure of appropriate broad-spectrum antibiotic treatment concomitant with lower respiratory tract infection symptoms, microbiological criteria with corresponding clinical signs and symptoms.
EVALUATION OF PARTICIPANTS' CLINICAL RESPONSE BASED ON CRITERIA: Complete Response: resolution of Invasive Fungal Infection (IFI) attributable symptoms, signs and laboratory or etiological abnormalities, if present at enrollment. Partial Response: clinically significant improvement in IFI attributable symptoms, signs and laboratory or etiological abnormalities, if present at enrollment, of which, one still had not achieved complete recession. Stable disease: no progress in IFI attributable symptoms, if present at enrollment. Failure: deterioration in IFI attributable clinical symptoms.
Treatment-emergent adverse events are defined as new events that occur following subject entry into the study or events that worsen following study entry state. Treatment-related adverse events are defined as new events that occur following subject entry into the study or events that worsen following study entry state and are judged by the investigator to be possibly, probably or definitely related to study medication.
Treatment-emergent adverse events are defined as new events that occur following subject entry into the study or events that worsen following study entry state. Treatment-related adverse events are defined as new events that occur following subject entry into the study or events that worsen following study entry state and are judged by the investigator to be possibly, probably or definitely related to study medication.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. Treatment-related AEs were determined by the investigator to be related to the drug. The 95% confidence interval (CI) was based on the exact binomial method by Clopper- Pearson.
Blood samples were collected for qualitative polymerase chain reaction (PCR) assay for Trypanosoma cruzi deoxyribonucleic acid (DNA). Successful response was defined as a negative qualitative PCR value at the Day 180 follow up visit.
Complete Response was defined as resolution of all attributable clinical signs and symptoms and radiologic and mycologic abnormalities, if present at baseline. Partial Response was defined as clinically meaningful improvement in attributable clinical signs and symptoms and radiologic and mycologic abnormalities, if present at baseline.
Characterization of the pharmacokinetics (PK) parameters of POS determined from plasma samples taken at steady-state after receiving IV administration of 300 mg POS twice a day (BID) on Day 1 and then 300 mg POS QD until at least Day 10. Steady-state Cavg, where Cavg is defined as AUC0-24hr divided by the dosing interval. Subgroup 1 - Serial PK, multiple same-day blood draw, performed specifically for determination of PK parameters of Cavg, AUC, Cmin, Cmax, Tmax and Total Body Clearance in addition to plasma trough determination. Subgroup 2 - Sparse PK, once a day blood draw, performed for plasma trough determination only.
Characterization of the PK parameters of POS determined from plasma samples taken at steady-state after receiving IV administration of 300 mg POS twice a day (BID) on Day 1 and then 300 mg POS QD until at least Day 10. Steady-state Cavg, where Cavg is defined as AUC0-24hr divided by the dosing interval. The percentage of participants with ssCavg ≥500 ng/mL are presented. Subgroup 1 - Serial PK, multiple same-day blood draw, performed specifically for determination of PK parameters of Cavg, AUC, Cmin, Cmax, Tmax and Total Body Clearance in addition to plasma trough determination. Subgroup 2 - Sparse PK, once a day blood draw, performed for plasma trough determination only.
Characterization of the PK parameters of POS determined from plasma samples taken at steady-state after receiving IV administration of 300 mg POS twice a day (BID) on Day 1 and then 300 mg POS QD until at least Day 10. AUC0-24 is defined as area under the plasma concentration-time curve from time 0 extrapolated to 24 hours. Subgroup 1 - Serial PK, multiple same-day blood draw, performed specifically for determination of PK parameters of Cavg, AUC, Cmin, Cmax, Tmax and Total Body Clearance in addition to plasma trough determination. Subgroup 2 - Sparse PK, once a day blood draw, performed for plasma trough determination only.
Characterization of the PK parameters of POS determined from plasma samples taken at steady-state after receiving IV administration of 300 mg POS twice a day (BID) on Day 1 and then 300 mg POS QD until at least Day 10. Cmax is defined as the maximum concentration of POS in plasma. Subgroup 1 - Serial PK, multiple same-day blood draw, performed specifically for determination of PK parameters of Cavg, AUC, Cmin, Cmax, Tmax and Total Body Clearance in addition to plasma trough determination. Subgroup 2 - Sparse PK, once a day blood draw, performed for plasma trough determination only.
Characterization of the PK parameters of POS determined from plasma samples taken at steady-state after receiving IV administration of 300 mg POS twice a day (BID) on Day 1 and then 300 mg POS QD until at least Day 10. Cmin is defined as the minimum concentration of POS in plasma. Subgroup 1 - Serial PK, multiple same-day blood draw, performed specifically for determination of PK parameters of Cavg, AUC, Cmin, Cmax, Tmax and Total Body Clearance in addition to plasma trough determination. Subgroup 2 - Sparse PK, once a day blood draw, performed for plasma trough determination only.
Characterization of the PK parameters of POS determined from plasma samples taken at steady-state after receiving IV administration of 300 mg POS twice a day (BID) on Day 1 and then 300 mg POS QD until at least Day 10. Tmax is defined as the time it takes to achieve maximum concentration of POS in plasma. Subgroup 1 - Serial PK, multiple same-day blood draw, performed specifically for determination of PK parameters of Cavg, AUC, Cmin, Cmax, Tmax and Total Body Clearance in addition to plasma trough determination. Subgroup 2 - Sparse PK, once a day blood draw, performed for plasma trough determination only.
Characterization of the PK parameters of POS determined from plasma samples taken at steady-state after receiving IV administration of 300 mg POS twice a day (BID) on Day 1 and then 300 mg POS QD until at least Day 10. CL is defined as the time it takes for POS to be completely removed from the body's blood stream. Subgroup 1 - Serial PK, multiple same-day blood draw, performed specifically for determination of PK parameters of Cavg, AUC, Cmin, Cmax, Tmax and Total Body Clearance in addition to plasma trough determination. Subgroup 2 - Sparse PK, once a day blood draw, performed for plasma trough determination only.
Pre-dose plasma trough concentrations by study day between serial PK and Sparse PK - where serial PK is defined as multiple serial blood sampling of more than 6 timepoints; and sparse PK is defined as few blood samples taken and single or limited timepoints
Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma AUC from time 0-24 hours post-dose (AUC0-24hr) of posaconazole. A non compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation.
Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma Cmax of posaconazole. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation.
Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma Cmin of posaconazole. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation.
Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma Cavg of posaconazole. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation.
Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma Tmax of posaconazole. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation.
Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma CL of posaconazole administered by IV. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for participants that received IV treatment.
Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma CL/F of posaconazole administered by PFS. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for participants that received PFS treatment.
The ssCavg was calculated in order to determine the percentage of participants achieving the pharmacokinetic (PK) target of ssCavg \>500 ng/mL on Day 8 when plasma drug levels had reached steady state.
The ssAUC0-24hr was calculated to determine the mean plasma drug concentration in the Intensive and Sparse PK subgroup from immediately after dosing to 24 hours post-dose on Day 8. Results data are presented as the arithmetic mean (% arithmetic coefficient of variation \[CV\]), where CV is calculated as (100 x standard deviation/arithmetic mean).
The ssCmax was calculated in order to determine the maximum post-dose plasma drug concentration in the Intensive and Sparse PK subgroup on Day 8. Results data are presented as the arithmetic mean (% arithmetic coefficient of variation \[CV\]), where CV is calculated as (100 x standard deviation/arithmetic mean).
The ssCmin was calculated in order to determine the lowest measurable drug concentration in the Intensive and Sparse PK subgroup up to 24 hours post-dose on Day 8. Results data are presented as the arithmetic mean (% arithmetic coefficient of variation \[CV\]), where CV is calculated as (100 x standard deviation/arithmetic mean).
The ssTmax was calculated in order to determine the amount of time required to reach ssCmax in the Intensive and Sparse PK subgroup on Day 8.
The AUC0-24hr was calculated to determine the mean plasma drug concentration from immediately after dosing to 24 hours post-dose in the Immediate and Sparse PK subgroup on Day 1. Results data are presented as the arithmetic mean (% arithmetic coefficient of variation \[CV\]), where CV is calculated as (100 x standard deviation/arithmetic mean).
The Cmax was calculated to determine the maximum plasma drug concentration up to 24 hours post-dose in the Immediate and Sparse PK subgroup on Day 1. Results data are presented as the arithmetic mean (% arithmetic coefficient of variation \[CV\]), where CV is calculated as (100 x standard deviation/arithmetic mean).
The Cmin was calculated in order to determine the lowest measurable drug concentration from immediately after dosing to 24 hours post-dose in the Immediate and Sparse PK subgroup on Day 1. Results data are presented as the arithmetic mean (% arithmetic coefficient of variation \[CV\]), where CV is calculated as (100 x standard deviation/arithmetic mean).
The Tmax was calculated in order to determine the time required to reach Cmax in the Immediate and Sparse PK subgroup on Day 1.
Blood samples were collected from participants for the determination of plasma POS concentration.
Blood samples were collected from participants for the determination of plasma POS concentration.
Blood samples were collected from participants for the determination of plasma POS concentration.
Blood samples were collected from participants for the determination of plasma POS concentration.
Blood samples were collected from participants for the determination of plasma POS concentration.
Blood samples were collected from participants for the determination of plasma POS concentration.
Blood samples were collected from participants for the determination of plasma POS concentration.
Blood samples were collected from participants for the determination of plasma POS concentration.
Blood samples were collected from participants for the determination of plasma POS concentration. Cavg was calculated as steady state AUC / dosing interval (24 hours).
Blood samples were collected from participants for the determination of plasma POS concentration.
Blood samples were collected from participants for the determination of plasma POS concentration.
Blood samples were collected from participants for the determination of plasma POS concentration.
Blood samples were collected from participants for the determination of plasma POS concentration.
Blood samples were collected from participants for the determination of plasma POS concentration.
Blood samples were collected from participants for the determination of plasma POS concentration. Cavg was calculated as steady state AUC / dosing interval (12 hours).
Blood samples were collected from participants for the determination of plasma POS concentration.
Posaconazole steady-state concentrations of posaconazole in the plasma reached after regular and repeated dosing were used to estimate pharmacokinetic (PK) parameters for each participant where Cavg was defined as area under the plasma concentration versus time curve divided by the dosing interval. Blood samples for the assessment of Cavg were collected on Day 1 and Day 8 predose and then at specified time points up to 24 hours postdose.
Cmin was defined as posaconazole trough level immediately before a participant received the dose of posaconazole tablets on the specified day. Trough (Cmin) level blood samples for determination of posaconazole in plasma were collected for all participants on Day 1, Day 2, Day 3, and Day 8. On Day 1, the trough level sample was collected the before the first dose of study drug. On Day 2, trough samples were collected approximately 12 hours after the second dose of study drug was administered on Day 1. On all subsequent days, trough samples were collected approximately 24 hours following the previous day's dose of study drug.
Blood samples for the assessment of Cmax were collected on Day 1 and Day 8 predose and then at specified time points up to 24 hours postdose.
Blood samples for the assessment of Tmax were collected on Day 1 and Day 8 predose and then at specified time points up to 24 hours postdose.
Blood samples for the assessment of CL/F, the rate at which posaconazole was removed from the body, were collected on Day 1 and Day 8 predose and then at specified time points up to 24 hours postdose.
| Arm | Type | Description |
|---|---|---|
| Cohort 1: Posaconazole | EXPERIMENTAL | 300 mg posaconazole oral tablet (or 300 mg intravenous (IV) solution) twice on Day 1, followed by 300 mg oral tablet or IV solution once daily for up to 84 days |
| Cohort 1: Voriconazole | ACTIVE_COMPARATOR | 300 mg voriconazole oral tablet (or 6 mg/kg IV solution) twice on Day 1, followed by 200 mg oral tablet (or 4 mg/kg IV solution) twice daily for up to 84 days |
| Cohort 2: Posaconazole | EXPERIMENTAL | 300 mg posaconazole oral tablet (or 300 mg intravenous (IV) solution) twice on Day 1, followed by 300 mg oral tablet or IV solution once daily for up to 84 days |
| Cohort 2: Voriconazole | ACTIVE_COMPARATOR | 300 mg voriconazole oral tablet (or 6 mg/kg IV solution) twice on Day 1, followed by 200 mg oral tablet (or 4 mg/kg IV solution) twice daily for up to 84 days |
| Posaconazole (POS) | EXPERIMENTAL | Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment. |
| Voriconazole | ACTIVE_COMPARATOR | Participants received 6 mg/kg voriconazole (VOR) IV twice per day (BID) on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment. |
| Posaconazole | ACTIVE_COMPARATOR | Posaconazole oral suspension 200 mg three times a day (TID) |
| Fluconazole | ACTIVE_COMPARATOR | Fluconazole 400 mg once daily (QD) |
| Placebo | PLACEBO_COMPARATOR | Posaconazole placebo (10 mL) oral suspension twice daily for 60 days |
| Posaconazole + Benznidazole | EXPERIMENTAL | Posaconazole 400 mg (10 mL) oral suspension twice daily for 60 days and benznidazole (BNZ) 100 mg oral tablet twice daily (200-mg daily dose) for 60 days |
| Benznidazole + Placebo | ACTIVE_COMPARATOR | Posaconazole placebo (10 mL) oral suspension twice daily for 60 days and benznidazole 100 mg oral tablet twice daily (200-mg daily dose) for 60 days |
| 3.5 mg/kg POS (2<7 years old) | EXPERIMENTAL | Children 2 to less than 7 years of age will receive POS at 3.5 mg/kg by intravenous (IV) solution twice on Day 1, then once daily on Days 2-10. This will be followed by treatment with 3.5 mg/kg POS once daily by powder for oral suspension (PFS) for a minimum of 10 days; or, if they are unwilling or unable to tolerate POS PFS, continued treatment with POS IV. |
| 4.5 mg/kg POS (2<7 years old) | EXPERIMENTAL | Children 2 to less than 7 years of age will receive POS at 4.5 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10. This will be followed by treatment with 4.5 mg/kg POS once daily by PFS for a minimum of 10 days; or, if they are unwilling or unable to tolerate POS PFS, continued treatment with POS IV. |
| 3.5 mg/kg POS (7-17 years old) | EXPERIMENTAL | Children 7 to 17 years of age will receive POS at 3.5 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10. This will be followed by treatment with 3.5 mg/kg POS once daily by PFS for a minimum of 10 days; or, if they are unwilling or unable to tolerate POS PFS, continued treatment with POS IV. |
| 4.5 mg/kg POS (7-17 years old) | EXPERIMENTAL | Children 7 to 17 years of age will receive POS at 4.5 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10. This will be followed by treatment with 4.5 mg/kg POS once daily by PFS for a minimum of 10 days; or, if they are unwilling or unable to tolerate POS PFS, continued treatment with POS IV. |
| 6 mg/kg POS (2<7 years old) | EXPERIMENTAL | Children 2 to less than 7 years of age will receive POS at 6 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10. This will be followed by treatment with 6 mg/kg POS once daily by PFS for a minimum of 10 days; or, if they are unwilling or unable to tolerate POS PFS, continued treatment with POS IV. |
| 6 mg/kg POS (7-17 years old) | EXPERIMENTAL | Children 7 to 17 years of age will receive POS at 6 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10. This will be followed by treatment with 6 mg/kg POS once daily by PFS for a minimum of 10 days; or, if they are unwilling or unable to tolerate POS PFS, continued treatment with POS IV. |
| POS IV 200 mg single dose (Cohort 0) | ACTIVE_COMPARATOR | POS 200 mg IV single dose infused over 1.5 hours on Day 1 followed 12 hours later by POS oral 400 mg, then by POS oral 400 mg BID on Days 2 through 6 and a single morning dose on Day 7 (Cohort 0) |
| Dextrose 5% in water (Cohort 0) | PLACEBO_COMPARATOR | Placebo IV single dose infused over 1.5 hours on Day 1 followed 12 hours later by POS oral 400 mg, then by POS oral 400 mg BID on Days 2 through 6 and a single morning dose on Day 7 (Cohort 0) |
| POS IV 200 mg BID (Cohort 1) | EXPERIMENTAL | POS 200 mg IV infused over 1.5 hours BID on Day 1, followed by POS 200 mg IV once daily on Days 2 through 14, then by POS 400 mg oral BID through Day 28 (Cohort 1) |
| POS IV 300 mg BID (Cohort 2) | EXPERIMENTAL | POS 300 mg IV infused over 1.5 hours BID on Day 1, followed by POS 300 mg IV once daily on Days 2 through 14, then by POS 400 mg oral BID through Day 28 (Cohort 2). After Day 5, POS IV was administered continuously or intermittently, depending on oral tolerability. |
| POS IV 300 mg BID (Cohort 3) | EXPERIMENTAL | POS 300 mg IV infused over 1.5 hours BID on Day 1, followed by POS 300 mg IV once daily on Days 2 through 5, then by POS 200 mg oral TID or POS 400 mg oral BID through Day 28, or POS 200-300 mg IV once daily as required (Cohort 3). After Day 5, POS IV was administered continuously or intermittently, depending on oral tolerability. |
| Posaconazole 200 mg | EXPERIMENTAL | Posaconazole 200 mg (two 100 mg tablets) twice daily (BID) on Day 1 followed by 200 mg (two 100 mg tablets) once daily (QD) for up to 28 days |
| Posaconazole 300 mg | EXPERIMENTAL | Posaconazole 300 mg (three 100 mg tablets) BID on Day 1 followed by 300 mg (three 100 mg tablets) QD for up to 28 days |
| Name | Type | Description |
|---|---|---|
| Posaconazole | DRUG | 300 mg posaconazole twice on Day 1, either by oral tablet or IV solution; followed by 300 mg once daily for up to 84 days |
| Voriconazole | DRUG | 300 mg voriconazole oral tablet (or 6 mg/kg IV solution) twice on Day 1, followed by 200 mg oral tablet (or 4 mg/kg IV solution) twice daily for up to 84 days |
| Placebo | DRUG | Matching placebo received for Posaconazole (IV and oral) or Voriconazole (oral) |
| Fluconazole | DRUG | 50 mg/capsule (2 capsules), 150 mg/capsule (2 capsules); 400 mg QD Treatment was continued with each cycle of chemotherapy until: * The onset of a proven or probable diagnosis of invasive fungal infection (IFI) * 3 chemotherapy cycles or * Total treatment duration up to 12 weeks (84 days) |
| Posaconazole oral suspension | DRUG | - |
| Posaconazole IV | DRUG | Posaconazole (POS) 6 mg/kg body weight by IV infusion |
| Posaconazole PFS | DRUG | Dosing based on weight-band taken orally |
| Posaconazole tablet | DRUG | POS tablet 300 mg taken orally |
| Placebo for posaconazole | DRUG | Placebo oral suspension |
| Benznidazole | DRUG | BNZ 100 mg oral tablet |
| Posaconazole IV solution | DRUG | Posaconazole by IV solution twice on Day 1, then once daily on Days 2-10. |
| Posaconazole powder for oral suspension | DRUG | Posaconazole once daily by PFS for a minimum of 10 days |
| Dextrose 5% in water | DRUG | - |
| Posaconazole 200 mg | DRUG | - |
| Posaconazole 300 mg | DRUG | - |
Inclusion Criteria: * Body weight \>=45 kg * Can be treated by taking tablet orally or intravenous (IV) formulation via central vein * Female has a negative pregnancy test * Female of non-childbearing potential; or if of childbearing potential, agrees to use proper combination of barrier method of ...
Posaconazole is an antifungal drug in Phase 3 development for the prevention and treatment of invasive fungal infections, including invasive aspergillosis, in patients with neutropenia or leukopenia. It is also studied for other fungal infections. It is being developed by Merck & Company, Inc. (MRK).
Posaconazole is a small molecule antifungal that works by inhibiting the synthesis of ergosterol, a key component of the fungal cell membrane. This action disrupts the fungal cell membrane, leading to cell death. It is being studied for use in patients with compromised immune systems who are at risk for invasive fungal infections.
Posaconazole is being developed by Merck & Company, Inc., a pharmaceutical company traded on the New York Stock Exchange under the ticker symbol MRK. The company is conducting clinical trials to evaluate the drug's efficacy and safety in treating and preventing invasive fungal infections.
Posaconazole is currently in Phase 3 clinical development for the treatment of invasive fungal infections. It is an investigational drug and has not yet been approved by regulatory authorities. The drug is also being studied in earlier phase trials for other indications, including Chagas disease.
Posaconazole has been studied in several clinical trials, including NCT00034671 and NCT00550732 for refractory fungal infections, NCT01377480 for Chagas disease, and NCT04665037 for invasive fungal infection in children under 2 years. These trials have enrolled a total of 1074 participants across various phases.
Posaconazole IV 6 mg/kg is a formulation and dosing regimen of Posaconazole. The drug is also known by this name, which specifies the intravenous administration at a dose of 6 mg per kilogram of body weight. This formulation is used in clinical studies to evaluate the drug's pharmacokinetics and efficacy.