A Phase IV, Open Label, 4-period Cross-over Study to Investigate a Drug Interaction Between Lamivudine and Sorbitol Oral Solutions in Healthy Volunteers
Condition: Infection, Human Immunodeficiency Virus
MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections
Intervention: Lamivudine; Sorbitol
Intervention description: 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; 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.
Intervention MeSH terms: Lamivudine; Sorbitol
Phase: Phase 4
Study type: Interventional
Primary purpose: Other
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 16.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Lamivudine; Safety; Sorbitol; Pharmacokinetics

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.
    

Eligibility criteria:

        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.

        Exclusion Criteria:

          -  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:

          1. The QTc is the QT interval corrected for heart rate according to Fridericia's formula,
             machine-read or manually over-read.

          2. 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.

          3. 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.

               -  History of sensitivity to any of the study medications, or components thereof or
                  a history of drug or other allergy that, in the opinion of the investigator or
                  Medical Monitor, contraindicates their participation.

               -  Creatinine clearance (CrCL) <60 mL/minutes (min).

               -  Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody
                  test result at screening or within 3 months prior to first dose of study
                  treatment.

               -  A positive pre-study drug/alcohol screen.

               -  A positive test for HIV antibody.

               -  Where participation in the study would result in donation of blood or blood
                  product in excess of 500 mL within 56 days.

               -  The participant has participated in a clinical trial and has received an
                  investigational product within the following time period prior to the first
                  dosing day in the current study: 30 days, 5 half-lives or twice the duration of
                  the biological effect of the investigational product (whichever is longer).

               -  Exposure to more than four new chemical entities within 12 months prior to the
                  first dosing day.