Pharmacokinetics and population pharmacodynamic analysis of lanreotide Autogel.

Somatostatin analogs are the first-line medical therapy for acromegaly, and the treatment of this disease has been simplified by the development of extended-release formulations of these analogs. Lanreotide is a somatostatin analog that is available either as the microparticle formulation, requiring 7- to 14-day dosing, or as the aqueous Autogel formulation, requiring 28-day dosing. This study investigated the pharmacokinetics and pharmacodynamics of lanreotide. Patients with acromegaly were given 5 injections of lanreotide microparticles, 30 mg, followed by 3 injections of lanreotide Autogel, at doses of 60, 90, or 120 mg every 28 days. The study was extended to a further 12 injections of lanreotide Autogel with dose titration. A total of 144 patients were recruited; 130 received 3 injections of lanreotide Autogel, and 130 completed the extension phase. Average minimum lanreotide concentrations (Cmin) at steady state were 1.949 +/- 0.619, 2.685 +/- 0.783, and 3.575 +/- 1.271 ng/mL for 60, 90, and 120 mg of lanreotide Autogel, respectively, showing a dose-proportional increase. Population pharmacodynamic analysis showed that the relationship between either formulation of lanreotide and serum growth hormone (GH) concentrations was best described using an inhibitory maximum response (Emax) model that allowed for the possibility of an incomplete inhibition of GH. Lanreotide elicited a maximum reduction in GH of 82%. Because patients were already being treated, baseline GH (E0) was estimated, and the value of 8.63 ng/mL was in agreement with the inclusion criteria of GH 10 ng/mL or less. The effectiveness of treatment was demonstrated by the median serum concentration of lanreotide, 1.13 ng/mL, required to lower GH to 2.5 ng/mL or less. The serum concentration that elicited half of the Emax (EC50) was estimated as 0.206 ng/mL, showing a high sensitivity to lanreotide, with a predictably high interpatient variability of 200.75% reflecting the range of dosing regimens needed to control GH.

Assessment of diclofenac permeation with different formulations: anti-inflammatory study of a selected formula.

The aim of this study was to improve the transdermal permeation of sodium diclofenac. Permeation studies were carried out in vitro using human skin (0.4 mm thick) from plastic surgery as a membrane. Four liquid formulations of 1% (w/w) sodium diclofenac were assayed: three ternary solvent systems (M4, M5, M6) and one microemulsion (M3). A 1% (w/w) solution of sodium diclofenac and a commercially available semisolid preparation were tested as reference formulations. The following permeation parameters for diclofenac were assessed: permeability coefficient, flux and drug permeated and retained in the skin at 24 h. The highest values of these parameters were obtained with formula M4, which contains transcutol 59.2%, oleic acid 14.9% and d-limonene 5% (w/w) as permeation enhancers. The anti-inflammatory activity of this formula was compared with that of the semisolid preparation on carrageenan-induced paw edema in rats. As expected from in vitro results, the M4 diclofenac delivery system showed higher activity than the semisolid preparation, both when applied locally (to the inflammation area) and when applied systemically (to the back). Neither treatment irritated the skin when tested on rabbits in a 72-h trial. These results suggest that topical delivery of sodium diclofenac with an absorption enhancer such as a mixture of oleic acid and d-limonene (M4) may be an effective medication for both dermal and subdermal injuries.