פורמולציית שחרור מתמשך [1-3,6-9]
✓ פורמולציה מתקדמת וחדשנית, המתבססת על שחרור דו-פאזי – מיידי ומתמשך (איור 1). המשמעות היא שההשפעה מתחילה עם הנטילה ונמשכת לאורך שעות רבות
✓ הפורמולציה החדשה מאפשרת הפחתת תדירות הנטילה, מעודדת היענות, היצמדות לטיפול ומניעת הדרדרות אפשרית ל-HG
✓ מבית היוצר של Diclectin – חברת Duchesnay הקנדית
✓ בטוח כמו Diclectin
CLINICAL PHARMACOLOGY [5]
Mechanism of Action
The mechanism of action of BONJESTA is unknown.
Pharmacokinetics
The pharmacokinetics of BONJESTA has been characterized in healthy non-pregnant adult women.
Absorption
In a single-dose, crossover clinical trial conducted in 48 healthy, premenopausal women under fasting conditions, one BONJESTA (20 mg doxylamine succinate and 20 mg pyridoxine) tablet was bioequivalent to two combination tablets of 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride based on the exposure (AUC) and peak concentration (Cmax) of doxylamine and baseline corrected pyridoxal 5′-phosphate. Mean ± SD plasma (whole blood for pyridoxal) pharmacokinetic (PK) parameters are summarized in Table 1.
Table 1 – Mean ± SD Single-Dose Pharmacokinetics of BONJESTA in Healthy Premenopausal Adult Women
In a multiple-dose, crossover clinical trial conducted in 31 healthy, premenopausal women, one BONJESTA (20 mg doxylamine succinate and 20 mg pyridoxine) tablet given twice daily for 11 days was bioequivalent to one combination tablet of 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride given three times daily (1 tablet in the morning, 1 tablet in the afternoon and 2 tablets at bedtime), based on the exposure (AUC) and peak concentration (Cmax) of doxylamine and baseline corrected pyridoxal 5′-phosphate. Mean ± SD plasma (whole blood for pyridoxal) PK parameters are summarized in Table 2.
Table 2 – Mean ± SD Multiple-Dose (Day 11) Pharmacokinetic Parameters of BONJESTA (given twice daily) in Healthy Premenopausal Adult Women
Food Effect
In a single-dose, crossover clinical trial conducted in 23 healthy, premenopausal women, the administration of a high fat, high calorie meal delayed the absorption of doxylamine, pyridoxine, and pyridoxine metabolites. This delay is associated with lower peak concentrations of doxylamine, pyridoxine, and pyridoxal. The extent of absorption for pyridoxine was decreased.
The effect of food on the peak concentration and the extent of absorption of the pyridoxine component is more complex because the pyridoxine metabolites such as pyridoxal, pyridoxamine, pyridoxal 5′-phosphate, and pyridoxamine 5′-phosphate also contribute to the biological activity. Food significantly reduces the bioavailability of pyridoxine, lowering its Cmax and AUC by approximately 67% and 37%, respectively, compared to fasting conditions. Similarly, food significantly reduces pyridoxal Cmax by approximately 46% compared to fasting conditions. In contrast, food did not affect pyridoxal 5′-phosphate Cmax and AUC.
Table 3 – Mean ± SD Pharmacokinetic Parameters of Doxylamine and Pyridoxine Metabolites Following a Single Dose Administration of BONJESTA Under Fed and Fasted Conditions in Healthy Premenopausal Adult Women
Distribution
Pyridoxine is highly protein bound, primarily to albumin. Its main active metabolite, pyridoxal 5′-phosphate (PLP) accounts for at least 60% of circulating vitamin B6 concentrations.
Metabolism
Doxylamine is biotransformed in the liver by N-dealkylation to its principle metabolites N-desmethyl-doxylamine and N, N-didesmethyldoxylamine.
Pyridoxine is a prodrug primarily metabolized in the liver.
Excretion
The principle metabolites of doxylamine, N-desmethyl-doxylamine and N, N-didesmethyldoxylamine, are excreted by the kidney.
The terminal elimination half-life of doxylamine and pyridoxine are 11.9 hours and 0.4 hours, respectively (see Table 4).
Table 4 – Terminal Elimination Half-Life (T1/2el) for BONJESTA Administered as a Single Dose under Fasting Conditions in Healthy Premenopausal Adult Women (N=23)
Use in Specific Populations
Race: No pharmacokinetic studies have been conducted related to race.
Hepatic Impairment: No pharmacokinetic studies have been conducted in hepatic impaired patients.
Renal Impairment: No pharmacokinetic studies have been conducted in renal impaired patients.