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

NCT02634073 | Completed Phase 4 Results

• 1 other identifier: 204857
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

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.

Conditions

Infection, Human Immunodeficiency Virus

Keywords

Lamivudine; Safety; Sorbitol; Pharmacokinetics

Outcome Measures

Primary Outcomes (5)

• 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.

  Day 1 to Day 3 in each treatment period

• 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.

  Day 1 to Day 3 in each treatment period

• 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.

  Day 1 to Day 3 in each treatment period

• Plasma Lamivudine Apparent Oral Clearance (CL/F)

  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

  Day 1 to Day 3 in each treatment period

• 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.

  Day 1 to Day 3 in each treatment period

Secondary Outcomes (15)

• Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Events (SAE)

  Up to 5 Weeks

• Change From Baseline in Pulse Rate

  Baseline and up to 5 weeks

• Change From Baseline in Body Temperature

  Baseline and up to 5 weeks

• Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

  Baseline and up to 5 weeks

• Number of Participants With Treatment Emergent Laboratory Abnormality Grade

  Up to Week 5

Study Arms (4)

Treatment A: Lamivudine 300 milligram(mg)

EXPERIMENTAL

Participant will receive single dose of Lamivudine 300 mg (30 ml of 10 mg/ml Oral Solution) after overnight fasting. Treatment period will be separated by at least 7 day wash out period.

Drug: Lamivudine

Treatment B: Lamivudine 300 mg + Sorbitol 3.2 g (low dose)

EXPERIMENTAL

Participant will receive single dose of Lamivudine 300 mg (30 ml of 10 mg/ml Oral Solution) + oral solution of Sorbitol 3.2 g after overnight fasting. Treatment period will be separated by at least 7 day wash out period.

Drug: Lamivudine; Drug: Sorbitol

Treatment C: Lamivudine 300 mg + Sorbitol 10.2 g (medium dose)

EXPERIMENTAL

Participant will receive single dose of Lamivudine 300 mg (30 ml of 10 mg/ml Oral Solution) + oral solution of Sorbitol 10.2 g after overnight fasting. Treatment period will be separated by at least 7 day wash out period

Drug: Lamivudine; Drug: Sorbitol

Treatment D: Lamivudine 300 mg + Sorbitol 13.4 g (high dose)

EXPERIMENTAL

Participant will receive single dose of Lamivudine 300 mg (30 ml of 10 mg/ml Oral Solution) + oral solution of Sorbitol 13.4 g after overnight fasting. Treatment period will be separated by at least 7 day wash out period

Drug: Lamivudine; Drug: Sorbitol

Interventions

Lamivudine DRUG

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

Treatment A: Lamivudine 300 milligram(mg); Treatment B: Lamivudine 300 mg + Sorbitol 3.2 g (low dose); Treatment C: Lamivudine 300 mg + Sorbitol 10.2 g (medium dose); Treatment D: Lamivudine 300 mg + Sorbitol 13.4 g (high dose)

Sorbitol DRUG

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.

Treatment B: Lamivudine 300 mg + Sorbitol 3.2 g (low dose); Treatment C: Lamivudine 300 mg + Sorbitol 10.2 g (medium dose); Treatment D: Lamivudine 300 mg + Sorbitol 13.4 g (high dose)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• ALT and bilirubin \>1.5x upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35 percent \[%\]).
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Participants with a pre-existing condition interfering with normal gastrointestinal anatomy or motility, hepatic and/or renal function, that could interfere with the absorption, metabolism, and/or excretion of the study drugs. Participants with a history of cholecystectomy, peptic ulceration, inflammatory bowel disease or pancreatitis should be excluded.
• Corrected QT (QTc) interval according to Fridericia's formula (QTcF) \> 450 milli-seconds (msec).
• Notes:
• The QTc is the QT interval corrected for heart rate according to Fridericia's formula, machine-read or manually over-read.
• The specific formula that will be used to determine eligibility and discontinuation for an individual participant should be determined prior to initiation of the study. In other words, several different formulae cannot be used to calculate the QTc for an individual participant and then the lowest QTc value used to include or discontinue the participant from the trial.
• For purposes of data analysis, Corrected QT interval according to Bazett's formula (QTcB), QTcF, another QT correction formula, or a composite of available values of QTc will be used as specified in the Reporting and Analysis Plan (RAP).
• Unable to refrain from the use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication until completion of the follow-up visit, unless in the opinion of the Investigator and Medical Monitor the medication will not interfere with the study procedures or compromise participant safety.
• History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of \>14 drinks for males or \>7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 millilitre \[mL\]) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
• Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
• Consumption of red wine, Seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of study medications.

Sponsors & Collaborators

• ViiV Healthcare: lead
• GlaxoSmithKline: collaborator

Study Sites (1)

GSK Investigational Site

Overland Park, Kansas, 66211, United States

Location

Related Publications (1)

• Adkison K, Wolstenholme A, Lou Y, Zhang Z, Eld A, Perger T, Vangerow H, Hayward K, Shaefer M, McCoig C. Effect of Sorbitol on the Pharmacokinetic Profile of Lamivudine Oral Solution in Adults: An Open-Label, Randomized Study. Clin Pharmacol Ther. 2018 Mar;103(3):402-408. doi: 10.1002/cpt.943. Epub 2017 Dec 11.

  PMID: 29150845 DERIVED

MeSH Terms

Conditions

Infections; Acquired Immunodeficiency Syndrome

Interventions

Lamivudine; Sorbitol

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Zalcitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Dideoxynucleosides; Sugar Alcohols; Alcohols; Organic Chemicals; Carbohydrates

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  ViiV Healthcare

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 14, 2015
• First Posted: December 17, 2015
• Study Start: January 1, 2016
• Primary Completion: March 1, 2016
• Study Completion: March 11, 2016
• Last Updated: May 15, 2017
• Results First Posted: May 15, 2017

Record last verified: 2017-02

Locations

US (1)