Gabapentin 800 mg tablets, four-way crossover, fasting bioavailability study in healthy subjects.

Rationale:

In clinical practice, generic drugs (generics) are often interchanged, whereas factual data regarding generic-generic interchangeability are lacking. Under these conditions, the so-called ‘shift’ or ‘drift’ problem that may occur when generics are interchanged may be reason for concern; while generics are exchangeable with the innovator product, generics themselves may not be, which may lead to loss of efficacy or increased toxicity. This problem may be relevant for certain drugs with a narrow therapeutic window, including anti-epileptic drugs, where seizure control may be lost or side-effects may increase when patients switch from one generic to another.

The aim of this study is to investigate the possible consequences of generic-generic substitution of gabapentin, a frequently used anti-epileptic drug.



Objectives:

To assess the pharmacokinetic profile, tolerability and safety of gabapentin of the brand Neurontin® 800 mg tablet and three generic gabapentin 800 mg tablets after single dose administration of 800 mg in healthy volunteers under fasting conditions.



Study design:

Randomized, four-period, four-treatment, crossover, balanced, single dose comparative oral bioavailability study in healthy, adult, subjects under fasting conditions.



Study population:

The study population will be non-smoking or moderate smoking healthy human volunteers with an age range from 18 - 55 years old.



Intervention:

There will be 4 periods of administration of gabapentin, each separated by one week. Each volunteer will receive a single dose of 800 mg of gabapentin after an overnight fast (either a brand Neurontin® tablet or one of the 3 generic gabapentin tablets in a randomized order) at the beginning of each period.



Main study endpoints:

The main endpoints will be the 90% confidence intervals of the ratio of least-squares means of the pharmacokinetic parameters AUC0-t, AUCinf, and Cmax of two tested gabapentin products (for all combinations among the four products).



Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

Study participants will undergo a medical history taking, physical examination (2 times), routine laboratory blood (6 times) and urine tests (2 times), urine pregnancy tests (5 times, females only), urine testing for recreational drugs (5 times), alcohol breath tests (5 times), a 12-lead ECG (2 times) and measurements of vital signs, i.e. heart rate, blood pressure, temperature and respiratory rate (38 times) and venous blood sampling for analysis of gabapentin plasma concentration (12 times by venapunction, 56 times by peripheral venous catheter). A total of 306 mL of blood will be sampled from each participant during the study. A repeated blood or urine sampling may be performed when deemed necessary to check or follow up an abnormal result from a previous sample.

After a screening visit, each participant will visit the trial centre 4 times for a night (from 22 pm) and day (till 12 hours after dosing), and will fast for at least 10 hours before dosing until 4 hours post-dose. Water will be restricted for one hour before and after dosing.

Gabapentin has been demonstrated to be safe in humans within the effective dosing range from 900 to 3600 mg/day. Participants will not benefit directly from participation.

The aim of this study is to investigate the possible consequences of generic-generic substitution of gabapentin, a frequently used anti-epileptic drug.

All subjects will be checked-in at the unit of DRUM at 10 pm for an overnight stay without intake of any food and drink at least after 10 pm. Drug screen test, pregnancy test and alcohol breath test are repeated between check-in and dosing. Limited lab safety (creatinin, total bilirubin, alkaline phosphatase, AST, ALT, gamma GT and glucose) is repeated within 2 hours before dosing. They will be housed in the unit to at least 12 hours post dose in each period. During this period, subjects will not be allowed to leave the unit. Subjects will return to the unit for the 24-, 36- and 48-hour blood sample.

There will be 4 periods of administration of gabapentin, each separated by one week. Each volunteer will receive a single dose of 800 mg of gabapentin after an overnight fast (either a brand Neurontin® tablet or one of the 3 generic gabapentin tablets in a randomized order) at the beginning of each period.