Innovative prolonged-release oral alkalising formulation allowing sustained urine pH increase with twice daily administration: randomised trial in healthy adults

Abstract

A multi-particulate fixed-dose combination product, consisting of a combination of two alkalising salts formulated as prolonged-release granules, ADV7103, was developed to obtain a sustained and prolonged alkalising effect. The specific release of both types of granules was shown in vitro through their dissolution profiles, which indicated that potassium citrate was released within the first 2-3 h and potassium bicarbonate up to 10-12 h after administration. The long-lasting coverage of ADV7103 was confirmed through a randomised, placebo-controlled, double-blind, two-period study, measuring its effect on urine pH in healthy adults (n = 16) at doses of alkalising agent ranging between 0.98 and 2.88 meq/kg/day. A significant increase of urine pH with a positive dose-response in healthy adult subjects was shown. Urine pH above 7 was maintained during 24 h with a dosing equivalent to 1.44 meq/kg twice a day, while urine pH was below 6 most of the time with placebo. The effect observed was non-saturating within the range of doses evaluated and the formulation presented a good safety profile. ADV7103 provided an effective prolonged release of alkalising salts to cover a 12-h effect with adequate tolerability and could afford a twice a day (morning and evening) dosing in patients requiring long-term treatment. Current alkalising treatments in adults and children generally consist of immediate-release forms of citrate or bicarbonate salts. The absorption of the actives is rapid, generating a peak of high alkaline load, and a short-lived effect. These treatments are characterized by inconvenient dosing schemes (3-6 daily doses), difficult day and night coverage and a jerky action leading to a variable efficacy, gastro-intestinal discomfort, and bad taste, which may result in poor acceptability and compliance 1,2. After oral administration, citrate undergoes oxidative metabolic breakdown to carbon dioxide (CO 2) or bicarbonate. Consequently, a basifying effect is associated with its metabolism 3. This salt is mainly absorbed under its divalent form (pH 4.8-6.4), and is thus known to have an absorption window limited to the upper side of the small intestine (duodenum, early part of the jejunum) 4. At physiological blood pH (7.4), citrate is entirely ionized in its trivalent form. Most of the citrate in the blood circulates unbound at relatively low (0.05 to 0.3 mmol/l) concentrations and the remaining quota is bound to calcium, potassium and sodium 5. In contrast, oral bicarbonate is absorbed all over the gastro-intestinal tract, independently of the local pH. A massive elimination of bicarbonate could occur in the stomach, since it neutralizes gastric acid with the production of CO 2 eliminated by the respiratory route. The remaining bicarbonate not involved in that reaction is rapidly absorbed by the intestinal mucosa 6-8. In order to maintain a sustained alkalising effect over 12 h with a good safety profile, ADV7103, a new prolonged-release oral formulation, was designed to maximise absorption of the active substances. ...

Living with Distal Renal Tubular Acidosis: Qualitative Research with Nephrologists, Patients, and Caregivers

“…Our interview ndings suggest that tolerability issues, bad taste, and the required frequency of dosing with existing medications for dRTA could be at the origin of most adherence issues in these patients. These ndings help support the need for therapeutic alternatives with a longer dosing interval 20 , improved safety, and gastrointestinal tolerability and palatability, for treatment of dRTA. 21,22 It has been reported that adherence to treatment declines as the number of daily doses increases, particularly in the case of chronic diseases.…”

Safety, efficacy, and acceptability of ADV7103 during 24 months of treatment: an open-label study in pediatric and adult patients with distal renal tubular acidosis

“…Adults (18 to 55 years old), adolescents (12 to 17 years old), children (4 to 11 years old), and infants and toddlers (6 months to 3 years old) were enrolled to continue their treatment with ADV7103 for at least 24 months at the optimal dose previously determined and further adapted if required. ADV7103 consists of prolonged-release granules, presented in 8 mEq and 24 mEq sachets containing roughly one part of potassium citrate and two parts of potassium bicarbonate [ 9 ]. The total daily dose was divided in two intakes, one in the morning and another in the evening, including one or several sachets.…”

“…A new oral granule formulation (ADV7103), which combines the advantages of potassium citrate and potassium bicarbonate, provides an effective prolonged release of alkalizing salts affording a 12-h effect with adequate tolerability [ 9 ].…”

Improved growth of a child with primary distal renal tubular acidosis after switching from a conventional alkalizing treatment to a new prolonged-release formulation containing potassium citrate and potassium bicarbonate: lessons for the clinical nephrologist

“…The main difference between both treatments is the sustained control during day and night that can be achieved with ADV7103 [9], but not with immediate release sodium bicarbonate twice daily. This can be explained by the pharmacokinetic and pharmacodynamic profiles of both formulations.…”