A Phase IV, Open Label, 4-period Cross-over Study to Investigate a Drug Interaction Between Lamivudine and Sorbitol Oral Solutions in Healthy Volunteers

An Open-label Single-Center, 4-Period William's Cross-Over Design Drug Interaction Trial to Determine the Effects of Sorbitol-Containing Solutions on Lamivudine Exposure Following Administration of Lamivudine Oral Solution in Healthy Adult Subjects

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02634073

Enrollment

Registered

2015-12-17

Start date

2016-01-01

Completion date

2016-03-11

Last updated

2017-05-15

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Infection, Human Immunodeficiency Virus

Keywords

Lamivudine, Safety, Sorbitol, Pharmacokinetics

Brief summary

Lamivudine (3TC) is a nucleoside analogue indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and children. Documented literature elucidates that simultaneous administration of multiple sorbitol-containing products could increase the potential for a significant interaction and may contribute to the lower 3TC exposures. In this study several sorbitol doses (3.2 gram (g), 10.2 g, and 13.4 g solutions) will be administered with lamivudine to investigate dose dependency and mimic the situation where multiple sorbitol-containing antiretroviral medications may be co-administered with lamivudine. It will be open label, randomized, 4-way crossover (by William's design method) design at a single centre. Randomized participants will receive a single dose of each of four treatments after wash out period of minimum 7 days.

Interventions

DRUGLamivudine

It is a clear, colorless to pale yellow solution with the odour of fruit. It will be provided in a 240 mL bottle with the strength of 10 mg/mL Lamivudine 300 mg (30 mL of solution) will be administered orally to the participants

DRUGSorbitol

It is a clear, colorless, odourless solution. It will be available in 3 dosage levels viz;. 3.2 g (low dose), 10.2 g (medium dose) and 13.4 g (high dose) sorbitol total dose.

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

OTHER

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

Yes

Inclusion criteria

* Between 18 and 65 years of age inclusive, at the time of signing the informed consent. * Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination and laboratory tests. * A participant with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or

Exclusion criteria

, outside the reference range for the population being studied may be included only if the investigator in consultation with the Medical Monitor if required agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. * Body weight \>=50 kilogram (kg) (110 pounds \[lb\]) for men and \>45 kg (99 lb) for women and body mass index (BMI) within the range 18.5 - 31 kg/meter square (m\^2) (inclusive). * Male or Female. Females A female participant is eligible to participate if she is not pregnant (as confirmed by a negative serum or urine human chorionic gonadotrophin (hCG) test), not lactating, and at least one of the following conditions applies: Non-reproductive potential defined as: Pre-menopausal females with one of the following: Documented tubal ligation or Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion or Hysterectomy or Documented Bilateral Oophorectomy; Postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. * Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the consent form and in the protocol.

Design outcomes

Primary

Measure	Time frame	Description
Plasma Lamivudine Area Under the Plasma Concentration Time Curve (AUC) From Time Zero to the Last Quantifiable Time Point (AUC[0-t]), AUC From Time Zero Extrapolated to Infinity (AUC[0-inf]) and AUC From Time Zero to 24 Hours (AUC[0-24])	Day 1 to Day 3 in each treatment period	Serial blood sample were collected at Pre-dose; 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36 and 48 hours post-dose in each treatment period. AUC was determined using the trapezoidal rule. Analysis of variance (ANOVA), considering treatment and period as fixed effects and participant as random effect, was performed using Mixed Linear Models procedure to compare the plasma lamivudine Pharmacokinetic (PK) parameters.
Plasma Lamivudine Maximum Observed Concentration (Cmax), Concentration at 24 Hour (h) Post-dose (C24) and Last Measurable Concentration (Ct)	Day 1 to Day 3 in each treatment period	Serial blood sample were collected at Pre-dose; 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36 and 48 hours post-dose in each treatment period. Time of the last measurable concentration (t) was 48 hours for all participants and all treatments. ANOVA, considering treatment and period as fixed effects and participant as random effect, was performed using Mixed Linear Models procedure to compare the plasma lamivudine PK parameters.
Lamivudine Elimination Half-life in Plasma (t1/2)	Day 1 to Day 3 in each treatment period	Serial blood sample were collected at Pre-dose; 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36 and 48 hours post-dose in each treatment period. ANOVA, considering treatment and period as fixed effects and participant as random effect, was performed using Mixed Linear Models procedure to compare the plasma lamivudine t1/2.
Plasma Lamivudine Apparent Oral Clearance (CL/F)	Day 1 to Day 3 in each treatment period	Serial blood sample were collected at Pre-dose; 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36 and 48 hours post-dose in each treatment period. ANOVA, considering treatment and period as fixed effects and participant as random effect, was performed using Mixed Linear Models procedure to compare the plasma lamivudine CL/F
Time to Observed Maximum Lamivudine Plasma Concentration (Tmax), Time of Last Measurable Plasma Concentration (Tlast) and Absorption Lag Time in Plasma (Tlag)	Day 1 to Day 3 in each treatment period	Serial blood sample were collected at Pre-dose; 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36 and 48 hours post-dose in each treatment period.

Secondary

Measure	Time frame	Description
Change From Baseline in Erythrocytes	Baseline and up to 5 weeks	Blood samples were collected at Day -1, Day 3 of every treatment period and at follow-up. Change from Baseline for erythrocytes was calculated as the post-dose visit value minus the value at Baseline, at Day 3 and Follow-up. Baseline value used in the analysis was the latest pre-dose values on Day 1 of each treatment/Period. Day -1 presented the Baseline absolute values; Day 3 and Follow-Up presented the changes from Baseline.
Change From Baseline in Hematocrit	Baseline and up to 5 weeks	Blood samples were collected at Day -1, Day 3 of every treatment period and at follow-up. Change from Baseline for hematocrit was calculated as the post-dose visit value minus the value at Baseline, at Day 3 and Follow-up. Baseline value used in the analysis was the latest pre-dose values on Day 1 of each treatment/period. Day -1 presented the Baseline absolute values; Day 3 and Follow-Up presented the changes from Baseline.
Change From Baseline in Hemoglobin	Baseline and up to 5 weeks	Blood samples were collected at Day -1, Day 3 of every treatment period and at follow-up. Change from Baseline for hemoglobin was calculated as the post-dose visit value minus the value at Baseline, at Day 3 and Follow-up. Baseline value used in the analysis was the latest pre-dose values on Day 1 of each treatment/period. Day -1 presented the Baseline absolute values; Day 3 and Follow-Up presented the changes from Baseline.
Change From Baseline in Mean Corpuscular Hemoglobin (MCH)	Baseline and up to 5 weeks	Blood samples were collected at Day -1, Day 3 of every treatment period and at follow-up. Change from Baseline for MCH was calculated as the post-dose visit value minus the value at Baseline, at Day 3 and Follow-up. Baseline value used in the analysis was the latest pre-dose values on Day 1 of each treatment/period. Day -1 presented the Baseline absolute values; Day 3 and Follow-Up presented the changes from Baseline.
Change From Baseline in Mean Corpuscular Volume (MCV)	Baseline and up to 5 weeks	Blood samples were collected at Day -1, Day 3 of every treatment period and at follow-up. Change from Baseline for MCV was calculated as the post-dose visit value minus the value at Baseline, at Day 3 and Follow-up. Baseline value used in the analysis was the latest pre-dose values on Day 1 of each treatment/period. Day -1 presented the Baseline absolute values; Day 3 and Follow-Up presented the changes from Baseline.
Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Events (SAE)	Up to 5 Weeks	An AE is any untoward medical occurrence, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect or event that may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition.
Change From Baseline in Blood Urea Nitrogen (BUN), Sodium, Potassium, Glucose, Calcium	Baseline and up to 5 weeks	Blood samples were collected at Day -1, Day 3 of every treatment period and at follow-up. Change from Baseline for BUN, sodium, potassium, glucose, calcium were calculated as the post-dose visit value minus the value at Baseline, at Day 3 and Follow-up. Baseline value used in the analysis was the latest pre-dose values on Day 1 of each treatment/period. Day -1 presented the Baseline absolute values; Day 3 and Follow-Up presented the changes from Baseline.
Change From Baseline in Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) and Alkaline Phosphates	Baseline and up to 5 weeks	Blood samples were collected at Day -1, Day 3 of every treatment period and at follow-up. Change from Baseline for AST, ALT and alkaline phosphatase were calculated as the post-dose visit value minus the value at Baseline, at Day 3 and Follow-up. Baseline value used in the analysis was the latest pre-dose values on Day 1 of each treatment/period. Day -1 presented the Baseline absolute values; Day 3 and Follow-Up presented the changes from Baseline.
Change From Baseline in Creatinine, Total Bilirubin and Direct Bilirubin	Baseline and up to 5 weeks	Blood samples were collected at Day -1, Day 3 of every treatment period and at follow-up. Change from Baseline for creatinine and direct bilirubin were calculated as the post-dose visit value minus the value at Baseline, at Day 3 and Follow-up. Baseline value used in the analysis was the latest pre-dose values on Day 1 of each treatment/period. Change from Baseline in total bilirubine was not assessed. Day -1 presented the Baseline absolute values; Day 3 and Follow-Up presented the changes from Baseline.
Change From Baseline in Albumin	Baseline and up to 5 weeks	Blood samples were collected at Day -1, Day 3 of every treatment period and at follow-up. Change from Baseline for albumin was calculated as the post-dose Visit Value minus the value at Baseline, at Day 3 and Follow-up. Baseline value used in the analysis was the latest pre-dose values on Day 1 of each treatment/Period. Day -1 presented the Baseline absolute values; Day 3 and Follow-Up presented the changes from Baseline.
Change From Baseline in Platelets, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils	Baseline and up to 5 weeks	Blood samples were collected at Day -1, Day 3 of every treatment period and at follow-up. Change from Baseline for platelets, neutrophils, lymphocytes, monocytes, eosinophils, basophils were calculated as the post-dose visit value minus the value at Baseline, at Day 3 and Follow-up. Baseline value used in the analysis was the latest pre-dose values on Day 1 of each treatment/period. Day -1 presented the Baseline absolute values; Day 3 and Follow-Up presented the changes from Baseline.
Change From Baseline in Pulse Rate	Baseline and up to 5 weeks	Change from Baseline for pulse rate was calculated as the post-dose visit value minus the value at Baseline, at Day 3 and Follow-up. Baseline value used in the analysis was the latest pre-dose values on Day 1 of each treatment/period.
Change From Baseline in Body Temperature	Baseline and up to 5 weeks	Change from Baseline for body temperature was calculated as the post-dose visit value minus the value at Baseline, at Day 3 and Follow-up. Baseline value used in the analysis was the latest pre-dose values on Day 1 of each treatment/period.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)	Baseline and up to 5 weeks	Change from Baseline for DBP and SBP was calculated as the post-dose visit value minus the value at Baseline, at Day 3 and Follow-up. Baseline value used in the analysis was the latest pre-dose values on Day 1 of each treatment/period.
Number of Participants With Treatment Emergent Laboratory Abnormality Grade	Up to Week 5	Division of Acquired immune deficiency syndrome (DAIDS) Table AE grades 1, 2, 3, and 4 of laboratory abnormalities were applied and grade were summarized by treatment and day and were listed by participant, treatment, day, and actual date and time. Treatment emergent grades are defined as any new toxicity grades or the worsened grades compared to Baseline grade. Treatment emergent lab abnormality Grade 1 for aspartate aminotransferase and sodium at follow-up visit are summarized.

Countries

United States

Participant flow

Pre-assignment details

Sixteen subjects were randomized to one of the 4 treatment sequences separated by \>=7 day washout between doses.

Participants by arm

Arm	Count
All Treatment Groups Combined Sixteen participants were randomized to receive one of the following 4 treatment sequences : Treatment sequence 1 : ABCD; Treatment sequence 2: DABC; Trearment sequence 3: BCDA; Treatment sequence 4: CDAB; where A: Lamivudine 300 mg, B: Lamivudine 300 mg+ Sorbitol 3.2 g, C: Lamivudine 300 mg+ Sorbitol 10.2 g, D: Lamivudine 300 mg+ Sorbitol 13.4 g.	16
Total	16

Baseline characteristics

Characteristic	All Treatment Groups Combined
Age, Continuous	40.6 Years STANDARD_DEVIATION 12.3
Race/Ethnicity, Customized African American/African Heritage	6 Participants
Race/Ethnicity, Customized White - White/Caucasian/European Heritage	10 Participants
Sex: Female, Male Female	2 Participants
Sex: Female, Male Male	14 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	1 / 16	2 / 16	1 / 16	1 / 16
serious Total, serious adverse events	0 / 16	0 / 16	0 / 16	0 / 16

Outcome results

Primary

Lamivudine Elimination Half-life in Plasma (t1/2)

Serial blood sample were collected at Pre-dose; 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36 and 48 hours post-dose in each treatment period. ANOVA, considering treatment and period as fixed effects and participant as random effect, was performed using Mixed Linear Models procedure to compare the plasma lamivudine t1/2.

Time frame: Day 1 to Day 3 in each treatment period

Population: PK Summary Population

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
A: Lamivudine 300 mg	Lamivudine Elimination Half-life in Plasma (t1/2)	13.9 Hour (Hr)	Geometric Coefficient of Variation 20.9
B: Lamivudine 300 mg + Sorbitol 3.2 g	Lamivudine Elimination Half-life in Plasma (t1/2)	19.0 Hour (Hr)	Geometric Coefficient of Variation 40.6
C: Lamivudine 300 mg + Sorbitol 10.2 g	Lamivudine Elimination Half-life in Plasma (t1/2)	21.2 Hour (Hr)	Geometric Coefficient of Variation 47.3
D: Lamivudine 300 mg + Sorbitol 13.4 g	Lamivudine Elimination Half-life in Plasma (t1/2)	17.3 Hour (Hr)	Geometric Coefficient of Variation 48.6

90% CI: [1.11, 1.69]ANCOVA

90% CI: [1.25, 1.88]ANCOVA

90% CI: [1.04, 1.61]ANCOVA

Primary

Plasma Lamivudine Apparent Oral Clearance (CL/F)

Time frame: Day 1 to Day 3 in each treatment period

Population: PK Summary Population

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
A: Lamivudine 300 mg	Plasma Lamivudine Apparent Oral Clearance (CL/F)	22.738 Liter (L)/hr	Geometric Coefficient of Variation 22.3
B: Lamivudine 300 mg + Sorbitol 3.2 g	Plasma Lamivudine Apparent Oral Clearance (CL/F)	26.621 Liter (L)/hr	Geometric Coefficient of Variation 21.2
C: Lamivudine 300 mg + Sorbitol 10.2 g	Plasma Lamivudine Apparent Oral Clearance (CL/F)	33.608 Liter (L)/hr	Geometric Coefficient of Variation 22.1
D: Lamivudine 300 mg + Sorbitol 13.4 g	Plasma Lamivudine Apparent Oral Clearance (CL/F)	34.875 Liter (L)/hr	Geometric Coefficient of Variation 24.1

90% CI: [1.094, 1.251]ANCOVA

90% CI: [1.386, 1.576]ANCOVA

90% CI: [1.466, 1.684]ANCOVA

Primary

Plasma Lamivudine Area Under the Plasma Concentration Time Curve (AUC) From Time Zero to the Last Quantifiable Time Point (AUC[0-t]), AUC From Time Zero Extrapolated to Infinity (AUC[0-inf]) and AUC From Time Zero to 24 Hours (AUC[0-24])

Serial blood sample were collected at Pre-dose; 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36 and 48 hours post-dose in each treatment period. AUC was determined using the trapezoidal rule. Analysis of variance (ANOVA), considering treatment and period as fixed effects and participant as random effect, was performed using Mixed Linear Models procedure to compare the plasma lamivudine Pharmacokinetic (PK) parameters.

Time frame: Day 1 to Day 3 in each treatment period

Population: PK Summary Population: defined as participants who had valid lamivudine PK parameter estimates from both reference and test treatments. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
A: Lamivudine 300 mg	Plasma Lamivudine Area Under the Plasma Concentration Time Curve (AUC) From Time Zero to the Last Quantifiable Time Point (AUC[0-t]), AUC From Time Zero Extrapolated to Infinity (AUC[0-inf]) and AUC From Time Zero to 24 Hours (AUC[0-24])	AUC (0-inf); n=16, 14, 16, 13	13.2 hour (h)*microgram (mcg)/milliliter (mL)	Geometric Coefficient of Variation 22.3
A: Lamivudine 300 mg	Plasma Lamivudine Area Under the Plasma Concentration Time Curve (AUC) From Time Zero to the Last Quantifiable Time Point (AUC[0-t]), AUC From Time Zero Extrapolated to Infinity (AUC[0-inf]) and AUC From Time Zero to 24 Hours (AUC[0-24])	AUC (0-t) ; n=16, 16, 16, 16	12.9 hour (h)*microgram (mcg)/milliliter (mL)	Geometric Coefficient of Variation 23
A: Lamivudine 300 mg	Plasma Lamivudine Area Under the Plasma Concentration Time Curve (AUC) From Time Zero to the Last Quantifiable Time Point (AUC[0-t]), AUC From Time Zero Extrapolated to Infinity (AUC[0-inf]) and AUC From Time Zero to 24 Hours (AUC[0-24])	AUC (0-24) ; n=16, 16, 16, 16	12.4 hour (h)*microgram (mcg)/milliliter (mL)	Geometric Coefficient of Variation 23.6
B: Lamivudine 300 mg + Sorbitol 3.2 g	Plasma Lamivudine Area Under the Plasma Concentration Time Curve (AUC) From Time Zero to the Last Quantifiable Time Point (AUC[0-t]), AUC From Time Zero Extrapolated to Infinity (AUC[0-inf]) and AUC From Time Zero to 24 Hours (AUC[0-24])	AUC (0-inf); n=16, 14, 16, 13	11.3 hour (h)*microgram (mcg)/milliliter (mL)	Geometric Coefficient of Variation 21.2
B: Lamivudine 300 mg + Sorbitol 3.2 g	Plasma Lamivudine Area Under the Plasma Concentration Time Curve (AUC) From Time Zero to the Last Quantifiable Time Point (AUC[0-t]), AUC From Time Zero Extrapolated to Infinity (AUC[0-inf]) and AUC From Time Zero to 24 Hours (AUC[0-24])	AUC (0-t) ; n=16, 16, 16, 16	10.6 hour (h)*microgram (mcg)/milliliter (mL)	Geometric Coefficient of Variation 21.6
B: Lamivudine 300 mg + Sorbitol 3.2 g	Plasma Lamivudine Area Under the Plasma Concentration Time Curve (AUC) From Time Zero to the Last Quantifiable Time Point (AUC[0-t]), AUC From Time Zero Extrapolated to Infinity (AUC[0-inf]) and AUC From Time Zero to 24 Hours (AUC[0-24])	AUC (0-24) ; n=16, 16, 16, 16	9.96 hour (h)*microgram (mcg)/milliliter (mL)	Geometric Coefficient of Variation 22.6
C: Lamivudine 300 mg + Sorbitol 10.2 g	Plasma Lamivudine Area Under the Plasma Concentration Time Curve (AUC) From Time Zero to the Last Quantifiable Time Point (AUC[0-t]), AUC From Time Zero Extrapolated to Infinity (AUC[0-inf]) and AUC From Time Zero to 24 Hours (AUC[0-24])	AUC (0-24) ; n=16, 16, 16, 16	7.54 hour (h)*microgram (mcg)/milliliter (mL)	Geometric Coefficient of Variation 23.7
C: Lamivudine 300 mg + Sorbitol 10.2 g	Plasma Lamivudine Area Under the Plasma Concentration Time Curve (AUC) From Time Zero to the Last Quantifiable Time Point (AUC[0-t]), AUC From Time Zero Extrapolated to Infinity (AUC[0-inf]) and AUC From Time Zero to 24 Hours (AUC[0-24])	AUC (0-inf); n=16, 14, 16, 13	8.93 hour (h)*microgram (mcg)/milliliter (mL)	Geometric Coefficient of Variation 22.1
C: Lamivudine 300 mg + Sorbitol 10.2 g	Plasma Lamivudine Area Under the Plasma Concentration Time Curve (AUC) From Time Zero to the Last Quantifiable Time Point (AUC[0-t]), AUC From Time Zero Extrapolated to Infinity (AUC[0-inf]) and AUC From Time Zero to 24 Hours (AUC[0-24])	AUC (0-t) ; n=16, 16, 16, 16	8.21 hour (h)*microgram (mcg)/milliliter (mL)	Geometric Coefficient of Variation 22.9
D: Lamivudine 300 mg + Sorbitol 13.4 g	Plasma Lamivudine Area Under the Plasma Concentration Time Curve (AUC) From Time Zero to the Last Quantifiable Time Point (AUC[0-t]), AUC From Time Zero Extrapolated to Infinity (AUC[0-inf]) and AUC From Time Zero to 24 Hours (AUC[0-24])	AUC (0-inf); n=16, 14, 16, 13	8.60 hour (h)*microgram (mcg)/milliliter (mL)	Geometric Coefficient of Variation 24.1
D: Lamivudine 300 mg + Sorbitol 13.4 g	Plasma Lamivudine Area Under the Plasma Concentration Time Curve (AUC) From Time Zero to the Last Quantifiable Time Point (AUC[0-t]), AUC From Time Zero Extrapolated to Infinity (AUC[0-inf]) and AUC From Time Zero to 24 Hours (AUC[0-24])	AUC (0-t) ; n=16, 16, 16, 16	7.55 hour (h)*microgram (mcg)/milliliter (mL)	Geometric Coefficient of Variation 26.8
D: Lamivudine 300 mg + Sorbitol 13.4 g	Plasma Lamivudine Area Under the Plasma Concentration Time Curve (AUC) From Time Zero to the Last Quantifiable Time Point (AUC[0-t]), AUC From Time Zero Extrapolated to Infinity (AUC[0-inf]) and AUC From Time Zero to 24 Hours (AUC[0-24])	AUC (0-24) ; n=16, 16, 16, 16	6.91 hour (h)*microgram (mcg)/milliliter (mL)	Geometric Coefficient of Variation 28.9

90% CI: [0.799, 0.914]ANCOVA

90% CI: [0.635, 0.721]ANCOVA

90% CI: [0.594, 0.682]ANCOVA

90% CI: [0.747, 0.864]ANCOVA

90% CI: [0.566, 0.655]ANOVA

90% CI: [0.518, 0.599]ANCOVA

90% CI: [0.766, 0.876]ANCOVA

90% CI: [0.595, 0.68]ANCOVA

90% CI: [0.548, 0.626]ANCOVA

Primary

Plasma Lamivudine Maximum Observed Concentration (Cmax), Concentration at 24 Hour (h) Post-dose (C24) and Last Measurable Concentration (Ct)

Serial blood sample were collected at Pre-dose; 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36 and 48 hours post-dose in each treatment period. Time of the last measurable concentration (t) was 48 hours for all participants and all treatments. ANOVA, considering treatment and period as fixed effects and participant as random effect, was performed using Mixed Linear Models procedure to compare the plasma lamivudine PK parameters.

Time frame: Day 1 to Day 3 in each treatment period

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
A: Lamivudine 300 mg	Plasma Lamivudine Maximum Observed Concentration (Cmax), Concentration at 24 Hour (h) Post-dose (C24) and Last Measurable Concentration (Ct)	C24	0.036 mcg/mL	Geometric Coefficient of Variation 25.1
A: Lamivudine 300 mg	Plasma Lamivudine Maximum Observed Concentration (Cmax), Concentration at 24 Hour (h) Post-dose (C24) and Last Measurable Concentration (Ct)	Cmax	3.34 mcg/mL	Geometric Coefficient of Variation 34.9
A: Lamivudine 300 mg	Plasma Lamivudine Maximum Observed Concentration (Cmax), Concentration at 24 Hour (h) Post-dose (C24) and Last Measurable Concentration (Ct)	Ct	0.013 mcg/mL	Geometric Coefficient of Variation 28.4
B: Lamivudine 300 mg + Sorbitol 3.2 g	Plasma Lamivudine Maximum Observed Concentration (Cmax), Concentration at 24 Hour (h) Post-dose (C24) and Last Measurable Concentration (Ct)	C24	0.036 mcg/mL	Geometric Coefficient of Variation 31.1
B: Lamivudine 300 mg + Sorbitol 3.2 g	Plasma Lamivudine Maximum Observed Concentration (Cmax), Concentration at 24 Hour (h) Post-dose (C24) and Last Measurable Concentration (Ct)	Cmax	2.42 mcg/mL	Geometric Coefficient of Variation 32.7
B: Lamivudine 300 mg + Sorbitol 3.2 g	Plasma Lamivudine Maximum Observed Concentration (Cmax), Concentration at 24 Hour (h) Post-dose (C24) and Last Measurable Concentration (Ct)	Ct	0.017 mcg/mL	Geometric Coefficient of Variation 26.3
C: Lamivudine 300 mg + Sorbitol 10.2 g	Plasma Lamivudine Maximum Observed Concentration (Cmax), Concentration at 24 Hour (h) Post-dose (C24) and Last Measurable Concentration (Ct)	Ct	0.019 mcg/mL	Geometric Coefficient of Variation 38.7
C: Lamivudine 300 mg + Sorbitol 10.2 g	Plasma Lamivudine Maximum Observed Concentration (Cmax), Concentration at 24 Hour (h) Post-dose (C24) and Last Measurable Concentration (Ct)	C24	0.041 mcg/mL	Geometric Coefficient of Variation 21.8
C: Lamivudine 300 mg + Sorbitol 10.2 g	Plasma Lamivudine Maximum Observed Concentration (Cmax), Concentration at 24 Hour (h) Post-dose (C24) and Last Measurable Concentration (Ct)	Cmax	1.60 mcg/mL	Geometric Coefficient of Variation 27.2
D: Lamivudine 300 mg + Sorbitol 13.4 g	Plasma Lamivudine Maximum Observed Concentration (Cmax), Concentration at 24 Hour (h) Post-dose (C24) and Last Measurable Concentration (Ct)	C24	0.039 mcg/mL	Geometric Coefficient of Variation 21.6
D: Lamivudine 300 mg + Sorbitol 13.4 g	Plasma Lamivudine Maximum Observed Concentration (Cmax), Concentration at 24 Hour (h) Post-dose (C24) and Last Measurable Concentration (Ct)	Cmax	1.52 mcg/mL	Geometric Coefficient of Variation 30.9
D: Lamivudine 300 mg + Sorbitol 13.4 g	Plasma Lamivudine Maximum Observed Concentration (Cmax), Concentration at 24 Hour (h) Post-dose (C24) and Last Measurable Concentration (Ct)	Ct	0.018 mcg/mL	Geometric Coefficient of Variation 51.5

90% CI: [0.916, 1.08]ANCOVA

90% CI: [1.03, 1.21]ANCOVA

90% CI: [1, 1.18]ANCOVA

90% CI: [1.13, 1.56]ANCOVA

90% CI: [1.25, 1.71]ANCOVA

90% CI: [1.18, 1.63]ANCOVA

90% CI: [0.657, 0.798]ANCOVA

90% CI: [0.434, 0.527]ANCOVA

90% CI: [0.412, 0.5]ANCOVA

Primary

Time to Observed Maximum Lamivudine Plasma Concentration (Tmax), Time of Last Measurable Plasma Concentration (Tlast) and Absorption Lag Time in Plasma (Tlag)

Serial blood sample were collected at Pre-dose; 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36 and 48 hours post-dose in each treatment period.

Time frame: Day 1 to Day 3 in each treatment period

Arm	Measure	Group	Value (MEDIAN)
A: Lamivudine 300 mg	Time to Observed Maximum Lamivudine Plasma Concentration (Tmax), Time of Last Measurable Plasma Concentration (Tlast) and Absorption Lag Time in Plasma (Tlag)	tmax	0.75 Hr
A: Lamivudine 300 mg	Time to Observed Maximum Lamivudine Plasma Concentration (Tmax), Time of Last Measurable Plasma Concentration (Tlast) and Absorption Lag Time in Plasma (Tlag)	tlag	0.000 Hr
A: Lamivudine 300 mg	Time to Observed Maximum Lamivudine Plasma Concentration (Tmax), Time of Last Measurable Plasma Concentration (Tlast) and Absorption Lag Time in Plasma (Tlag)	tlast	48.00 Hr
B: Lamivudine 300 mg + Sorbitol 3.2 g	Time to Observed Maximum Lamivudine Plasma Concentration (Tmax), Time of Last Measurable Plasma Concentration (Tlast) and Absorption Lag Time in Plasma (Tlag)	tmax	1.000 Hr
B: Lamivudine 300 mg + Sorbitol 3.2 g	Time to Observed Maximum Lamivudine Plasma Concentration (Tmax), Time of Last Measurable Plasma Concentration (Tlast) and Absorption Lag Time in Plasma (Tlag)	tlag	0.000 Hr
B: Lamivudine 300 mg + Sorbitol 3.2 g	Time to Observed Maximum Lamivudine Plasma Concentration (Tmax), Time of Last Measurable Plasma Concentration (Tlast) and Absorption Lag Time in Plasma (Tlag)	tlast	48.00 Hr
C: Lamivudine 300 mg + Sorbitol 10.2 g	Time to Observed Maximum Lamivudine Plasma Concentration (Tmax), Time of Last Measurable Plasma Concentration (Tlast) and Absorption Lag Time in Plasma (Tlag)	tlast	48.00 Hr
C: Lamivudine 300 mg + Sorbitol 10.2 g	Time to Observed Maximum Lamivudine Plasma Concentration (Tmax), Time of Last Measurable Plasma Concentration (Tlast) and Absorption Lag Time in Plasma (Tlag)	tmax	1.00 Hr
C: Lamivudine 300 mg + Sorbitol 10.2 g	Time to Observed Maximum Lamivudine Plasma Concentration (Tmax), Time of Last Measurable Plasma Concentration (Tlast) and Absorption Lag Time in Plasma (Tlag)	tlag	0.000 Hr
D: Lamivudine 300 mg + Sorbitol 13.4 g	Time to Observed Maximum Lamivudine Plasma Concentration (Tmax), Time of Last Measurable Plasma Concentration (Tlast) and Absorption Lag Time in Plasma (Tlag)	tmax	1.26 Hr
D: Lamivudine 300 mg + Sorbitol 13.4 g	Time to Observed Maximum Lamivudine Plasma Concentration (Tmax), Time of Last Measurable Plasma Concentration (Tlast) and Absorption Lag Time in Plasma (Tlag)	tlag	0.000 Hr
D: Lamivudine 300 mg + Sorbitol 13.4 g	Time to Observed Maximum Lamivudine Plasma Concentration (Tmax), Time of Last Measurable Plasma Concentration (Tlast) and Absorption Lag Time in Plasma (Tlag)	tlast	48.00 Hr

Secondary

Change From Baseline in Albumin

Blood samples were collected at Day -1, Day 3 of every treatment period and at follow-up. Change from Baseline for albumin was calculated as the post-dose Visit Value minus the value at Baseline, at Day 3 and Follow-up. Baseline value used in the analysis was the latest pre-dose values on Day 1 of each treatment/Period. Day -1 presented the Baseline absolute values; Day 3 and Follow-Up presented the changes from Baseline.