Pharmacodynamics, Safety and Pharmacokinetics of BMS-663068, an HIV Attachment Inhibitor, in HIV-1

HIV Infections Clinical Trial

Official title:

Randomized, Open Label, Multiple-Dose Study to Evaluate the Pharmacodynamics, Safety and Pharmacokinetics of BMS-663068 in HIV-1 Infected Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01009814
• Other study ID #: 206267
• Secondary ID: AI438-006
• Status: Completed
• Phase: Phase 2
• Start date: November 23, 2009
• Est. completion date: June 25, 2010

Study information

• Verified date: October 2019
• Source: ViiV Healthcare
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Research Hypothesis: Administration of BMS-663068, a prodrug for HIV attachment inhibitor BMS-626529, will result in a mean decrease of at least 1 log10 in HIV RNA at Day 9 following 8 days of therapy in at least one dosing regimen that is safe and well tolerated in Clade B HIV-1 infected subjects.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: June 25, 2010
• Est. primary completion date: June 25, 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Clade B HIV-1 infected subjects meeting following criteria at screening:

• Plasma HIV RNA = 5,000 copies/mL

• CD4+ lymphocyte = 200 cells/µL

• Antiretroviral naive or experienced

• Off all ARV therapy with HIV activity for > 8 weeks

• BMI of 18 to 35 kg/m2, inclusive.

• Not currently co-infected with HCV or HBV

• Men and women, = 18 years of age

Exclusion Criteria:

• Woman of childbearing potential (WOCBP) unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period up to 12 weeks after the last dose of study drug.

• WOCBP using prohibited contraceptive method including oral, injectable, or implantable hormonal contraceptive agent within 12 weeks of enrollment.

• Women who are pregnant or breastfeeding.

• Women with positive pregnancy test on enrollment or prior to study drug intake.

• Sexually active fertile men not using effective birth control during study and for at least 12 weeks after last dose of study drug if partners are WOCBP.

• Significant acute or chronic medical illness not stable or not controlled with medication or not consistent with HIV infection.

• Current or recent (within 3 months) gastrointestinal disease that, in the opinion of Investigator or Medical Monitor, may impact on drug absorption and/or put subject at risk for GI tract irritation and/or bleeding.

• Acute diarrhea lasting = 1 day, within 3 weeks prior to randomization.

• Major surgery within 4 weeks of study drug intake.

• Gastrointestinal surgery that could impact upon absorption of study drug.

• Donation of blood or plasma to blood bank or in a clinical study (except a Screening visit or follow up visit of less than 50 mL) within 4 weeks of study drug intake.

• Blood transfusion within 4 weeks of study drug intake.

• Inability to tolerate oral medication.

• Inability to be venipunctured and/or tolerate venous access.

• Personal history of clinically relevant cardiac disease, symptomatic or asymptomatic arrhythmias, syncopal episodes, or additional risk factors for torsades de pointes.

• Personal or family history of long QT syndrome.

• Recent (within 6 months) drug/alcohol abuse

• Any other medical, psychiatric and/or social reason which, in the opinion of the Investigator, would make the candidate inappropriate for participation.

• Evidence of organ dysfunction or clinically significant deviation from normal in physical examination, vital signs, ECG or clinical lab determinations or not consistent with subject's degree of HIV infection.

• Evidence of 2nd or 3rd degree heart block at screening or Day -1

• Positive urine drug screen at Screening or Day -1 without valid prescription (subjects positive for cannabinoids and/or amphetamines will be included).

• Positive blood screen for hepatitis B surface antigen.

• Positive blood screen for hepatitis C antibody and hepatitis C RNA.

• History of significant drug allergy

• Exposure to any investigational drug or placebo within 4 weeks of study drug intake.

• Prescription drugs within 4 weeks prior to study drug intake, unless approved by BMS medical monitor.

• Other drugs, including over-the-counter medications, vitamins and/or herbal preparations, within 1 week prior to study drug intake, unless approved by BMS medical monitor.

• Use of oral, injectable or implantable hormonal contraceptive agent within 12 weeks of study drug intake.

• Use of prescription drugs or OTC drugs that may cause GI tract irritation or bleeding within 2 weeks of study drug intake, unless approved by BMS medical monitor.

• Use of alcohol-containing beverages within 3 days prior to study drug intake.

• Use of grapefruit, grapefruit-containing or Seville orange-containing products within 7 days prior to study drug intake.

• Prisoners or subjects involuntarily incarcerated.

• Subjects compulsorily detained for treatment of either a psychiatric or physical illness.

Related Conditions & MeSH terms

• HIV Infections

Intervention

Drug:
• BMS-663068
BMS-663068 will be administered as a tablet formulation
• Ritonavir
Ritonavir will be administered as a capsule.

Locations

Country	Name	City	State
Germany	GSK Investigational Site	Berlin

Sponsors (2)

Lead Sponsor	Collaborator
ViiV Healthcare	GlaxoSmithKline

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean Logarithm With Base 10 (Log10) Change From Baseline in Human Immunodeficiency Virus (HIV) Ribonucleic Acid (RNA) at Day 9	The primary assessment of the antiviral activity of BMS-663068 was assessed on the log10 change from Baseline in HIV RNA to Day 9. Baseline was the last non-missing observation before first dose (Day 1 pre-dose) and change from Baseline was calculated by subtracting Baseline value from post-Baseline visit value. An analysis of covariance (ANCOVA) model correcting for Baseline HIV viral load and treatment group was used to test the differences in mean log10 decrease in HIV RNA at Day 9 between 2 regimen groups by antiretroviral treatment history (ARV [antiretroviral] naive, ARV experienced, and combined [ARV naive + ARV experienced]). For the combined group (ARV naive +ARV experienced) an additional ANCOVA was used correcting also for treatment history as an additional covariate. Only Clade B participants were included in the population.	Baseline and Day 9
Secondary	Change From Baseline in Cluster of Differentiation 4 Positive (CD4+) Cell Count and Cluster of Differentiation 8 Positive (CD8+) Cell Count	Blood samples were collected for evaluation of CD4+ and CD8+ cells at Baseline (Day 1, pre-dose), Day 8, Day 15 (Follow up) and Day 50 (study discharge). Baseline was the last non-missing observation before first dose (Day 1 pre-dose) and change from Baseline was calculated by subtracting Baseline value from post-Baseline visit value.	Baseline (Day 1 pre-dose), Day 8, Day 15 and Day 50
Secondary	Change From Baseline in Percent CD4+ Cell Count and Percent CD8+ Cell Count	Blood samples were collected for evaluation of percent CD4+ and percent CD8+ cells at Baseline (Day 1, pre-dose), Day 8, Day 15 (Follow up) and Day 50 (study discharge). Baseline was the last non-missing observation before first dose (Day 1 pre-dose) and change from Baseline was calculated by subtracting Baseline visit value from post-Baseline visit value.	Baseline (Day 1 pre-dose), Day 8, Day 15 and Day 50
Secondary	Number of Participants With Treatment Emergent Non-serious Adverse Event (Non-SAE) and Serious AE (SAE)	An AE is any new untoward medical occurrence or worsening of a pre-existing medical condition in a participant or clinical investigation participant administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. Any untoward medical occurrence resulting in death, life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent serious outcomes were categorized as SAE. Treatment emergent adverse events (occurred after start of treatment) have been presented.Safety Population comprised of all randomized participants who used the trial medication at least once.	Up to 50 days
Secondary	Number of Participants With Any Abnormality in Physical Examination	A complete physical examination included, at a minimum, assessment of the Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. A brief physical examination included, at a minimum assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). Any abnormality found by investigator during physical examination were recorded. Number of participants with any abnormality in physical examination during study have been reported.	Up to 50 days
Secondary	Number of Participants With Worst-case Abnormalities in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)	Vital signs including DBP and SBP were recorded. Normal ranges were as following: For DBP, lower limit: value <55 millimeter of mercury (mmHg) and change <-20 mmHg; upper limit: value >90 mmHg and change >20 mmHg). For SBP, lower limit: value <90 mmHg and change <-10 mmHg; upper limit: value >140 mmHg and change >10 mmHg. Number of participants with worst-case abnormalities are presented. Worst-case abnormality was defined as: (1) Below Normal: at least one post-Baseline assessment was below normal range, and no post-Baseline assessment was above normal range. (2) Above Normal: at least one post-Baseline assessment was above normal range, and no post-Baseline assessment was below normal range. (3) Within Normal: all post-Baseline assessments were within normal range. It was to be considered as 'Missing' when there were no post-Baseline assessments.	Up to 50 days
Secondary	Number of Participants With Worst-case Abnormalities in Body Temperature, Respiratory Rate [RR], and Heart Rate [HR]	Vital signs (body temperature, RR, and HR) were recorded. Normal range were: For HR, lower limit: 55 beats per minute (bpm) and change <-15 bpm; upper limit: >100 bpm and change >30 bpm). For temperature, lower limit: 36.0 Celsius; upper limit: >37.5 Celsius or change >1.7 Celsius). For RR, lower limit: 8 breaths per minute; upper limit: >16 breaths per minute or change >10 breaths per minute. Number of participants with worst-case abnormalities are presented. Worst-case abnormality was defined as: (1) Below Normal: at least one post-Baseline assessment was below normal range, and no post-Baseline assessment was above normal range. (2) Above Normal: at least one post-Baseline assessment was above normal range, and no post-Baseline assessment was below normal range. (3) Within Normal: all post-Baseline assessments were within normal range. It was to be considered as 'Missing' when there were no post-Baseline assessments.	Up to 50 days
Secondary	Number of Participants With Worst-case Abnormalities in Electrocardiogram (ECG) Parameters	A 12-lead ECG was recorded during the study using an ECG machine that automatically measures ECG parameters. Normal range for ECG parameters were: PR interval (upper: 200 milliseconds [ms]); QRS (lower: 50 ms; upper: 120 ms); Corrected QT interval by Bazett formula (QTcB) (change from Baseline - increases by > 30 ms); Corrected QT interval by Fredericia formula (QTcF) (change from Baseline - increases by > 30 ms). Number of participants with worst-case abnormalities are presented which was defined as: (1) Below Normal: at least one post-Baseline assessment was below normal range, and no post-Baseline assessment was above normal range. (2) Above Normal: at least one post-Baseline assessment was above normal range, and no post-Baseline assessment was below normal range. Within Normal: all post-Baseline assessments were within normal range. It was to be considered as 'Missing' when there were no post-Baseline assessments.	Up to 50 days
Secondary	Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters	Laboratory parameters included hematology, clinical chemistry and urine parameters. Clinically significant abnormal laboratory findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Any abnormal laboratory test results which were considered clinically significant by the investigator were recorded on the case report form. Number of participants with any clinically significant abnormalities in laboratory parameters have been presented.	Up to 50 days
Secondary	Maximum Observed Plasma Concentration (Cmax) of BMS-626529 Following Q12H Dosing	Blood samples were collected at indicated time points to assess Cmax of BMS-626529 following Q12H dosing. Geometric mean and geometric coefficient of variation are presented for Day 1, Day 8 morning dose (Anti Meridiem [AM]), Day 8 evening dose (Post Meridiem [PM]) and Day 8 morning + evening dose (AM+PM). Pharmacokinetic parameter values were derived by non-compartmental methods. Pharmacokinetic (PK) Population was used which comprised of all participants who receive BMS-663068 and provided pharmacokinetic samples.	Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours
Secondary	Cmax of BMS-626529 Following QHS Dosing	Blood samples were collected at indicated time points to assess Cmax of BMS-626529 following QHS dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 1, Day 8 evening dose (PM) and Day 8 morning (AM) + evening dose (PM).	Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours
Secondary	Trough Observed Plasma Concentration (Ctrough) of BMS-626529 Following Q12H Dosing	Blood samples were collected at indicated time points to access Ctrough of BMS-626529 following Q12H dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 1, Days 5, 6, 7, 8, Day 8 morning dose (AM) and Day 8 evening dose (PM).	Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours; Days 5,6,7: pre-morning dose
Secondary	Ctrough of BMS-626529 Following QHS Dosing	Blood samples were collected at indicated time points to assess Ctrough of BMS-626529 following QHS dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 1, Days 5, 6, 7, 8 and Day 8 evening dose (PM).	Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours; Days 5,6,7: pre-evening dose
Secondary	Area Under the Concentration-time Curve in One Dosing Interval (AUC [Tau]) of BMS-626529 Following Q12H Dosing	Blood samples were collected at indicated time points to assess AUC (tau) of BMS-626529 following Q12H dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 1, Day 8 morning dose (AM) and Day 8 evening dose (PM).	Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours
Secondary	AUC (Tau) of BMS-626529 Following QHS Dosing	Blood samples were collected at indicated time points to assess AUC (tau) of BMS-626529 following QHS dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 1 and Day 8 evening dose (PM).	Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours
Secondary	Area Under the Concentration-time Curve Over a 24-hour Period (AUC [0-24]) of BMS-626529 Following Q12H Dosing	Blood samples were collected at indicated time points to assess AUC (0-24) of BMS-626529 following Q12H dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 8.	Day 8: pre-morning dose, 1,2,3,4,5,6,8,12, 13,14,15,16,17,18,20 hours
Secondary	AUC (0-24) of BMS-626529 Following QHS Dosing	Blood samples were collected at indicated time points to assess AUC (0-24) of BMS-626529 following QHS dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 8.	Day 8: pre-evening dose, 1,2,3,4,5,6,8 hours
Secondary	Accumulation Index (AI) of BMS-626529 Following Q12H Dosing	Blood samples were collected at indicated time points to assess Accumulation Index of BMS-626529 following Q12H dosing. AI was calculated as ratio of AUC(tau) at steady-state to AUC(tau) after the first dose. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 8 morning dose (AM).	Day 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours
Secondary	Accumulation Index of BMS-626529 Following QHS Dosing	Blood samples were collected at indicated time points to assess Accumulation Index of BMS-626529 following QHS dosing. AI was calculated as ratio of AUC(tau) at steady-state to AUC(tau) after the first dose. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 8 evening dose (PM).	Day 8: pre-evening dose, 1,2,3,4,5,6,8 hours
Secondary	Inhibitory Quotient (IQ) of BMS-626529 by Css,Avg and by Lowest Concentration of a Drug During Dosing Interval (Cmin) Following Q12H Dosing	Blood samples were collected at indicated time points to assess IQ of BMS-626529. Inhibitory quotient was calculated as the ratio of BMS-626529 in vivo exposure to in vitro measured protein binding adjusted EC90 (PBA-EC90). The following in vivo exposure measures were used in evaluating IQ: Cmin and Css,avg. Geometric mean and geometric coefficient of variation are presented.	Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours; Day 9: pre-dose, 4,12 hours; Day 10: pre-dose, 12 hours; Day 11: pre-dose; Days 5,6,7: pre-morning dose
Secondary	Inhibitory Quotient (IQ) of BMS-626529 by Css,Avg and by Lowest Concentration of a Drug During Dosing Interval (Cmin) Following QHS Dosing	Blood samples were collected at indicated time points to assess IQ of BMS-626529. Inhibitory quotient was calculated as the ratio of BMS-626529 in vivo exposure to in vitro measured protein binding adjusted EC90 (PBA-EC90). The following in vivo exposure measures were used in evaluating IQ: Cmin and Css,avg. Geometric mean and geometric coefficient of variation are presented.	Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours; Day 2: pre-evening dose, 12,16 hours; Day 9: pre-dose, 12,16 hours; Day 10: pre-dose, 12 hours; Day 11: pre-dose; Days 5,6,7: pre-evening dose
Secondary	Inhibitory Quotient of BMS-626529 by Ctrough Following Q12H Dosing	Blood samples were collected at indicated time points to assess IQ of BMS-626529. Inhibitory quotient was calculated as the ratio of BMS-626529 in vivo exposure to in vitro measured protein binding adjusted EC90 (PBA-EC90). The following in vivo exposure measure was used in evaluating IQ: Ctrough. Geometric mean and geometric coefficient of variation are presented.	Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours; Day 9: pre-dose, 4,12 hours; Day 10: pre-dose, 12 hours; Day 11: pre-dose; Days 5,6,7: pre-morning dose
Secondary	Inhibitory Quotient of BMS-626529 by Ctrough Following QHS Dosing	Blood samples were collected at indicated time points to assess IQ of BMS-626529. Inhibitory quotient was calculated as the ratio of BMS-626529 in vivo exposure to in vitro measured protein binding adjusted EC90 (PBA-EC90). The following in vivo exposure measure was used in evaluating IQ: Ctrough. Geometric mean and geometric coefficient of variation are presented.	Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours; Days 2: pre-evening dose, 12,16 hours; Day 9: pre-dose, 12,16 hours; Day 10: pre-dose, 12 hours; Day 11: pre-dose; Days 5,6,7: pre-evening dose
Secondary	Cmax of Ritonavir Following Q12H Dosing	Blood samples were collected at indicated time points to assess Cmax of ritonavir following Q12H dosing. Geometric mean and geometric coefficient of variation are presented for Day 1, Day 8 morning dose (AM), Day 8 evening dose (PM) and Day 8 morning + evening dose (AM+PM). Pharmacokinetic parameter values were derived by non-compartmental methods. PK Population was used which comprised of all participants who receive ritonavir and provided pharmacokinetic samples.	Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours
Secondary	Cmax of Ritonavir Following QHS Dosing	Blood samples were collected at indicated time points to assess Cmax of ritonavir following QHS dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 1, Day 8 evening dose (PM) and Day 8 morning (AM) + evening dose (PM).	Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours
Secondary	Ctrough of Ritonavir Following Q12H Dosing	Blood samples were collected at indicated time points to access Ctrough of ritonavir following Q12H dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 1, Days 5, 6, 7, 8, Day 8 morning dose (AM) and Day 8 evening dose (PM).	Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours; Days 5,6,7: pre-morning dose
Secondary	Ctrough of Ritonavir Following QHS Dosing	Blood samples were collected at indicated time points to assess Ctrough of ritonavir following QHS dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 1, Days 5, 6, 7, 8 and Day 8 evening dose (PM).	Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours; Days 5,6,7: pre-evening dose
Secondary	AUC (Tau) of Ritonavir Following Q12H Dosing	Blood samples were collected at indicated time points to assess AUC (tau) of ritonavir following Q12H dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 1, Day 8 morning dose (AM) and Day 8 evening dose (PM).	Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours
Secondary	AUC (Tau) of Ritonavir Following QHS Dosing	Blood samples were collected at indicated time points to assess AUC (tau) of ritonavir following QHS dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 1 and Day 8 evening dose (PM).	Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours
Secondary	AUC (0-24) of Ritonavir Following Q12H Dosing	Blood samples were collected at indicated time points to assess AUC (0-24) of ritonavir following Q12H dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 8.	Day 8: pre-morning dose, 1,2,3,4,5,6,8,12, 13,14,15,16,17,18,20 hours
Secondary	AUC (0-24) of Ritonavir Following QHS Dosing	Blood samples were collected at indicated time points to assess AUC (0-24) of ritonavir following QHS dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 8.	Day 8: pre-evening dose, 1,2,3,4,5,6,8 hours
Secondary	Accumulation Index of Ritonavir Following Q12H Dosing	Blood samples were collected at indicated time points to assess Accumulation Index of ritonavir following Q12H dosing. AI was calculated as ratio of AUC(tau) at steady-state to AUC(tau) after the first dose. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 8 morning dose (AM).	Day 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours
Secondary	Accumulation Index of Ritonavir Following QHS Dosing	Blood samples were collected at indicated time points to assess Accumulation Index of ritonavir following QHS dosing. AI was calculated as ratio of AUC(tau) at steady-state to AUC(tau) after the first dose. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 8 evening dose (PM).	Day 8: pre-evening dose, 1,2,3,4,5,6,8 hours