A Single Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of the Long-Acting Injectable of MK-5720 in Participants With Schizophrenia
Overview
- Phase
- Phase 1
- Intervention
- Placebo to MK-5720
- Conditions
- Schizophrenia
- Sponsor
- Merck Sharp & Dohme LLC
- Enrollment
- 17
- Locations
- 4
- Primary Endpoint
- Number of Participants Who Experience ≥1 Adverse Event (AE) in Period 1
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics (PK) of single ascending intramuscular doses of MK-5720, and the safety and tolerability of multiple once-daily oral doses of MK-8189, in participants with schizophrenia. The primary study hypothesis is that the administration of MK-5720 is safe and well tolerated.
Detailed Description
In Period 1, participants receive once-daily MK-8189 for 7 days, followed by a 72-hour washout. In Period 2, participants receive a single dose of MK-5720.
Investigators
Eligibility Criteria
Inclusion Criteria
- •The main inclusion criteria include but are not limited to the following:
- •Meets diagnostic criteria for schizophrenia or schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria with the onset of the first episode being no less than 2 years prior to screening and monotherapy with antipsychotics for treatment should be indicated
- •Has a history of receiving and tolerating antipsychotics medication within the usual dose range employed for schizophrenia
- •Can discontinue the use of all antipsychotic medication at least 5 days or 3 half-lives (which ever in longer) prior to the start of the treatment period and during the study
Exclusion Criteria
- •The main exclusion criteria include but are not limited to the following:
- •Is at imminent risk of self-harm, based on clinical interview and responses on the Columbia-Suicide Severity Rating Scale (C-SSRS), or of harm to others in the opinion of the investigator
- •Has history of mental retardation, borderline personality disorder, or organic brain syndrome
- •Has a history of neuroleptic malignant syndrome or moderate to severe tardive dyskinesia
- •Has a substance-induced psychotic disorder or behavioral disturbance thought to be due to substance abuse
- •Has a history of seizure disorder beyond childhood or is receiving treatment with any anticonvulsant to prevent seizures
- •Has a family history of sudden death
- •Has claustrophobia to a degree that prevents tolerance of magnetic resonance imaging (MRI) scanning procedure
- •Has a metallic implant of any sort that prevents MRI examination, or any other contraindication to MRI examination
- •Presents any concern by the investigator regarding safe participation in the study or for any other reason the investigator considers the participant inappropriate for participation in the study
Arms & Interventions
Panel C
Participants received 7 days of oral MK-8189 up to 16 mg or matched placebo treatment (Period 1), followed by a single IM injection of MK-5720 up to 140 mg or a dose matched placebo (Period 2).
Intervention: Placebo to MK-5720
Panel C
Participants received 7 days of oral MK-8189 up to 16 mg or matched placebo treatment (Period 1), followed by a single IM injection of MK-5720 up to 140 mg or a dose matched placebo (Period 2).
Intervention: MK-8189
Panel C
Participants received 7 days of oral MK-8189 up to 16 mg or matched placebo treatment (Period 1), followed by a single IM injection of MK-5720 up to 140 mg or a dose matched placebo (Period 2).
Intervention: Placebo to MK-8189
Panel A
Participants received 7 days of oral MK-8189 4 mg or matched placebo treatment (Period 1), followed by a single intramuscular (IM) injection of MK-5720 35 mg or a dose matched placebo (Period 2).
Intervention: MK-5720
Panel A
Participants received 7 days of oral MK-8189 4 mg or matched placebo treatment (Period 1), followed by a single intramuscular (IM) injection of MK-5720 35 mg or a dose matched placebo (Period 2).
Intervention: Placebo to MK-5720
Panel A
Participants received 7 days of oral MK-8189 4 mg or matched placebo treatment (Period 1), followed by a single intramuscular (IM) injection of MK-5720 35 mg or a dose matched placebo (Period 2).
Intervention: MK-8189
Panel A
Participants received 7 days of oral MK-8189 4 mg or matched placebo treatment (Period 1), followed by a single intramuscular (IM) injection of MK-5720 35 mg or a dose matched placebo (Period 2).
Intervention: Placebo to MK-8189
Panel B
Participants received 7 days of oral MK-8189 8 mg or matched placebo treatment (Period 1), followed by a single IM injection of MK-5720 70 mg or a dose matched placebo (Period 2).
Intervention: MK-5720
Panel B
Participants received 7 days of oral MK-8189 8 mg or matched placebo treatment (Period 1), followed by a single IM injection of MK-5720 70 mg or a dose matched placebo (Period 2).
Intervention: Placebo to MK-5720
Panel B
Participants received 7 days of oral MK-8189 8 mg or matched placebo treatment (Period 1), followed by a single IM injection of MK-5720 70 mg or a dose matched placebo (Period 2).
Intervention: MK-8189
Panel B
Participants received 7 days of oral MK-8189 8 mg or matched placebo treatment (Period 1), followed by a single IM injection of MK-5720 70 mg or a dose matched placebo (Period 2).
Intervention: Placebo to MK-8189
Panel C
Participants received 7 days of oral MK-8189 up to 16 mg or matched placebo treatment (Period 1), followed by a single IM injection of MK-5720 up to 140 mg or a dose matched placebo (Period 2).
Intervention: MK-5720
Panel D
Participants received 7 days of oral MK-8189 up to 24 mg or matched placebo treatment (Period 1), followed by a single IM injection of MK-5720 up to 280 mg or a dose matched placebo (Period 2).
Intervention: MK-5720
Panel D
Participants received 7 days of oral MK-8189 up to 24 mg or matched placebo treatment (Period 1), followed by a single IM injection of MK-5720 up to 280 mg or a dose matched placebo (Period 2).
Intervention: Placebo to MK-5720
Panel D
Participants received 7 days of oral MK-8189 up to 24 mg or matched placebo treatment (Period 1), followed by a single IM injection of MK-5720 up to 280 mg or a dose matched placebo (Period 2).
Intervention: MK-8189
Panel D
Participants received 7 days of oral MK-8189 up to 24 mg or matched placebo treatment (Period 1), followed by a single IM injection of MK-5720 up to 280 mg or a dose matched placebo (Period 2).
Intervention: Placebo to MK-8189
Panel E
Participants received 7 days of oral MK-8189 up to 48 mg or matched placebo treatment (Period 1), followed by a single IM injection of MK-5720 up to 560 mg or a dose matched placebo (Period 2).
Intervention: MK-5720
Panel E
Participants received 7 days of oral MK-8189 up to 48 mg or matched placebo treatment (Period 1), followed by a single IM injection of MK-5720 up to 560 mg or a dose matched placebo (Period 2).
Intervention: Placebo to MK-5720
Panel E
Participants received 7 days of oral MK-8189 up to 48 mg or matched placebo treatment (Period 1), followed by a single IM injection of MK-5720 up to 560 mg or a dose matched placebo (Period 2).
Intervention: MK-8189
Panel E
Participants received 7 days of oral MK-8189 up to 48 mg or matched placebo treatment (Period 1), followed by a single IM injection of MK-5720 up to 560 mg or a dose matched placebo (Period 2).
Intervention: Placebo to MK-8189
Panel F
Participants received 7 days of oral MK-8189 up to 48 mg or matched placebo treatment (Period 1), followed by a single IM injection of MK-5720 up to 560 mg or a dose matched placebo (Period 2), after a Pharmacokinetic (PK) break following Panel E.
Intervention: MK-5720
Panel F
Participants received 7 days of oral MK-8189 up to 48 mg or matched placebo treatment (Period 1), followed by a single IM injection of MK-5720 up to 560 mg or a dose matched placebo (Period 2), after a Pharmacokinetic (PK) break following Panel E.
Intervention: Placebo to MK-5720
Panel F
Participants received 7 days of oral MK-8189 up to 48 mg or matched placebo treatment (Period 1), followed by a single IM injection of MK-5720 up to 560 mg or a dose matched placebo (Period 2), after a Pharmacokinetic (PK) break following Panel E.
Intervention: MK-8189
Panel F
Participants received 7 days of oral MK-8189 up to 48 mg or matched placebo treatment (Period 1), followed by a single IM injection of MK-5720 up to 560 mg or a dose matched placebo (Period 2), after a Pharmacokinetic (PK) break following Panel E.
Intervention: Placebo to MK-8189
Outcomes
Primary Outcomes
Number of Participants Who Experience ≥1 Adverse Event (AE) in Period 1
Time Frame: Up to approximately 10 days
An adverse event (AE) is defined as 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. The number of participants who experienced one or more AEs is reported here for participants in Period 1. Per protocol, this outcome measure has been reported by panel and dose. As specified by the protocol, Period 2 has been analyzed separately and reported later in the record.
Number of Participants Who Experience ≥1 AE(s) in Period 2
Time Frame: Up to approximately 72 days
An adverse event (AE) is defined as 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. The number of participants who experienced one or more AEs is reported here for participants in Period 2. Per protocol, this outcome measure has been reported by panel and dose. As specified by the protocol, Period 1 has been analyzed separately and reported earlier in the record.
Number of Participants Who Discontinue Study Due to an AE in Period 1
Time Frame: Up to approximately 10 days
An adverse event (AE) is defined as 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. The number of participants who discontinued study treatment due to an AE is reported here for participants in Period 1. Per protocol, this outcome measure has been reported by panel and dose. As specified by the protocol, Period 2 has been analyzed separately and reported later in the record.
Number of Participants Who Discontinue Study Due to an AE in Period 2
Time Frame: Up to approximately 72 days
An adverse event (AE) is defined as 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. The number of participants who discontinued study treatment due to an AE is reported here for participants in Period 2. Per protocol, this outcome measure has been reported by panel and dose. As specified by the protocol, Period 1 has been analyzed separately and reported earlier in the record.
Apparent Terminal Half-life (t1/2) of MK-5720
Time Frame: Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose
t1/2 is defined as the time required to divide plasma concentration of MK-5720 by half after reaching pseudo-equilibrium. Blood samples were collected at specified intervals for the determination t1/2 following a single dose administration of MK-5720 in Period 2. Per protocol, this outcome measure has been reported by panel and dose.
Area Under the Concentration-Time Curve From Time 0 to Last Quantifiable Concentration (AUC0-last) of MK-5720
Time Frame: Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose
AUC0-last was defined as the area under the concentration-time curve from time zero to time of last measurable concentration of MK-5720. Blood samples were collected at specified intervals were used to estimate AUC0-last following a single dose administration of MK-5720 in Period 2. Per protocol, this outcome measure has been reported by panel and dose.
Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC-inf) of MK-5720
Time Frame: Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose
AUC0-inf is defined as the area under concentration-time curve of MK-5720 from time zero to infinity. Blood samples were collected at specified intervals for the determination of AUC-inf following a single dose administration of MK-5720 in Period 2. Per protocol, this outcome measure has been reported by panel and dose.
Maximum Serum Concentration (Cmax) of MK-5720
Time Frame: Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose
Cmax is defined as the maximum concentration of MK-5720 reached. Blood samples were collected at specified intervals for the determination of Cmax following a single dose administration of MK-5720 in Period 2. Per protocol, this outcome measure has been reported by panel and dose.
Time to Maximum Concentration (Tmax) of MK-5720
Time Frame: Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose
Tmax is defined as the time to maximum concentration of MK-5720 reached. Blood samples were collected at specified intervals for the determination of Tmax following a single dose administration of MK-5720 in Period 2. Per protocol, this outcome measure has been reported by panel and dose.
Apparent Clearance (CL/F) of MK-5720
Time Frame: Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose
CL/F is the rate at which the MK-5720 is completely removed from plasma. Blood samples were collected at specified intervals for the determination of CL/F following a single dose administration of MK-5720 in Period 2. Per protocol, this outcome measure has been reported by panel and dose.
Apparent Volume of Distribution (Vz/F) of MK-5720
Time Frame: Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose
Vz/F is the apparent volume of distribution of MK-5720. Blood samples were collected at specified intervals for the determination of Vz/F following a single dose administration of MK-5720 in Period 2. Per protocol, this outcome measure has been reported by panel and dose.
Area Under the Concentration-Time Curve From Time 0 to 28 Days (AUC0-28d) of MK-8189
Time Frame: Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, and 672 hours postdose
AUC0-28d is defined as the area under the concentration-time curve from time zero to 28 days of MK-8189 (a metabolite of MK-5720). Blood samples were collected at specified intervals for the determination of AUC0-28d for MK-8189 following a single dose administration of MK-5720 in Period 2. Per protocol, this outcome measure has been reported by panel and dose.
AUC0-inf of MK-8189
Time Frame: Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose
AUC0-inf is defined as the area under concentration-time curve from time zero to infinity of MK-8189 (a metabolite of MK-5720). Blood samples were collected at specified intervals for the determination of AUC0-inf for MK-8198 following a single dose administration of MK-5720 in Period 2. Per protocol, this outcome measure has been reported by panel and dose.
Cmax of MK-8189
Time Frame: Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose
Cmax is defined as the maximum concentration of MK-8189 (a metabolite of MK-5720) reached. Blood samples were collected at specified intervals for the determination of Cmax for MK-8198 following a single dose administration of MK-5720 in Period 2. Per protocol, this outcome measure has been reported by panel and dose.
Tmax of MK-8189
Time Frame: Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose
Tmax is defined as the time to maximum concentration of MK-8189 (a metabolite of MK-5720). Blood samples were collected at specified intervals for the determination of Tmax for MK-8198 following a single dose administration of MK-5720 in Period 2. Per protocol, this outcome measure has been reported by panel and dose.
Concentration at Day 28 (C28d) of MK-8189
Time Frame: Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, and 672 hours postdose
C28d is defined as the maximum concentration from time zero to 28 days of MK-8189 (a metabolite of MK-5720). Blood samples were collected at specified intervals for the determination of C28d for MK-8198 following a single dose administration of MK-5720 in Period 2. Per protocol, this outcome measure has been reported by panel and dose. In cases where C28d values were below the limit of quantitation, geometric mean was not calculable and indicated as "NA."
CL/F of MK-8189
Time Frame: Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose
CL/F is the rate at which the MK-8189 (a metabolite of MK-5720) is completely removed from plasma. Blood samples were collected at specified intervals for the determination of CL/F for MK-8198 following a single dose administration of MK-5720 in Period 2. Per protocol, this outcome measure has been reported by panel and dose.
Vz/F of MK-8189
Time Frame: Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose
Vz/F is the apparent volume of distribution of MK-8189 (a metabolite of MK-5720). Blood samples were collected at specified intervals for the determination of Vz/F for MK-8198 following a single dose administration of MK-5720 in Period 2. Per protocol, this outcome measure has been reported by panel and dose.
t1/2 of MK-8189
Time Frame: Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose
t1/2 is defined as the time required to divide plasma concentration of MK-8189 (a metabolite of MK-5720) by half after reaching pseudo-equilibrium. Blood samples were collected at specified intervals for the determination of Half-life (t1/2) for MK-8198 following a single dose administration of MK-5720 in Period 2. Per protocol, this outcome measure has been reported by panel and dose.
Secondary Outcomes
- Panels D, E, and F: C28d Tied to Specific Exposures of MK-8189(Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, and 672 postdose)
- Panels C, D, E, and F: AUC0-28d of MK-8189 in Gluteal Muscle Versus AUC0-28 of MK-8189 in Deltoid Muscle(Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, and 672 hours postdose)
- Panels C, D, E, and F: AUC0-inf of MK-8189 in Gluteal Muscle Versus AUC0-inf of MK-8189 in Deltoid Muscle(Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose)
- Panels C, D, E, and F: Cmax of MK-8189 in Gluteal Muscle Versus Cmax of MK-8189 in Deltoid Muscle(Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose)
- Panels C, D, E, and F: Tmax of MK-8189 in Gluteal Muscle Versus Tmax of MK-8189 in Deltoid Muscle(Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, 1320 hours postdose)
- Panels C, D, E, and F: C28d of MK-8189 in Gluteal Muscle Versus C28d in Deltoid Muscle(Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, and 672 hours postdose)
- Panels C, D, E, and F: CL/F of MK-8189 in Gluteal Muscle Versus CL/F in Deltoid Muscle(Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose)
- Panels C, D, E, and F: Vz/F of MK-8189 in Gluteal Muscle Versus Vz/F of MK-8189 in Deltoid Muscle(Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose)
- Panels C, D, E, and F: t1/2 of MK-8189 in Gluteal Muscle Versus t1/2 of MK-8189 in Deltoid Muscle(Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose)
- Panels C, D, E, and F: AUC0-last of MK 5720 in Gluteal Muscle Versus AUC0-last of MK-5720 in Deltoid Muscle(Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose)
- Panels C, D, E, and F: AUC0-inf of MK-5720 in Gluteal Muscle Versus AUC0-inf of MK-5720 in Deltoid Muscle(Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose)
- Panels C, D, E, and F: Cmax of MK-5720 in Gluteal Muscle Versus Cmax of MK-5720 in Deltoid Muscle(Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose)
- Panels C, D, E, and F: Tmax of MK-5720 in Gluteal Muscle Versus Tmax of MK-5720 in Deltoid Muscle(Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose)
- Panels C, D, E, and F: CL/F of MK-5720 in Gluteal Muscle Versus CL/F of MK-5720 in Deltoid Muscle(Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose)
- Panels C, D, E, and F: Vz/F of MK-5720 in Gluteal Muscle Versus Vz/F of MK-5720 in Deltoid Muscle(Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose)
- Panels C, D, E, and F: t1/2 of MK-5720 in Gluteal Muscle Versus t1/2 of MK-5720 in Deltoid Muscle(Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours postdose)