Method of treating a child with central precocious puberty using an extended release composition

A method of treating central precocious puberty (CPP), comprising administering a dose of 45 mg leuprolide acetate to pediatric patients 2 years of age or older with CPP by subcutaneous injection, and continuing administration of the 45 mg leuprolide acetate to the pediatric patients by subcutaneous injection once every 6 months,

• wherein the leuprolide acetate is administered as a uniform suspension in an extended release composition comprising (a) a biodegradable polymer comprising polymers selected from 85:15 poly(lactic acid-co-glycolic acid) (PLGA) copolymers, 85:15 poly(lactide-co-glycolide) (PLG) copolymers, or a combination thereof, wherein the polymer has substantially no titratable carboxylic acid groups and at least one distal end group of the polymer is hydroxyl-terminated, and wherein the polymer is dissolved in (b) N-methyl-2-pyrrolidone (NMP),
• wherein the extended release composition delivers 45 mg leuprolide acetate in a 0.375 mL injection volume,
• wherein following administration into the pediatric patient the NMP dissipates out of the extended release formulation and an in situ solid depot is formed,
• wherein the in situ solid depot releases leuprolide acetate into the pediatric patient for a period of about 6 months and provides an initial burst phase of release of leuprolide acetate with a mean maximum serum leuprolide concentration in the range of 215.7 ng/ml which peaks at about 4 hours after the initial injection of the 45 mg leuprolide acetate dose followed by a plateau phase of release of the leuprolide acetate, wherein the serum leuprolide acetate concentration ranges from 0.18 ng/mL to 0.63 ng/ml from 4 weeks to 48 weeks with a mean of 0.37 ng/ml, and
• wherein the method provides a suppression of peak stimulated LH concentrations to less than 4 IU/L after 12 months treatment in more than 80% of pediatric patients being treated, based on evaluation in a group of pediatric patients having a mean age of 7.5 years at the start of treatment.

A method of treating central precocious puberty (CPP), comprising

• (i) administering a dose of 45 mg leuprolide acetate to pediatric patients 2 years of age or older with CPP by subcutaneous injection, and continuing administration of the 45 mg leuprolide acetate to the pediatric patients by subcutaneous injection once every 6 months,
• wherein the leuprolide acetate is administered as a uniform suspension in an extended release composition comprising (a) a biodegradable polymer comprising polymers selected from 85:15 poly(lactic acid-co-glycolic acid) (PLGA) copolymers, 85:15 poly(lactide-co-glycolide) (PLG) copolymer segments, or a combination thereof, wherein the polymer has substantially no titratable carboxylic acid groups and at least one distal end group of the polymer is hydroxyl-terminated, and wherein the polymer is dissolved in (b)N-methyl-2-pyrrolidone (NMP),
• wherein the extended release composition delivers 45 mg leuprolide acetate in a 0.375 mL injection volume,
• wherein following administration into the pediatric patient the NMP dissipates out of the extended release formulation and an in situ solid depot is formed, and
• wherein the in situ solid depot releases leuprolide acetate into the pediatric patient for a period of about 6 months,
• (ii) monitoring the pediatric patient's response to the administration of the 45 mg leuprolide acetate by evaluating a GnRH agonist stimulation test, basal serum luteinizing hormone (LH) levels or serum concentration of sex steroid levels in order to confirm suppression of pituitary gonadotropins, sex steroids and progression of secondary sexual characteristics, and
• (iii) if suppression is confirmed, continuing administration of the 45 mg leuprolide acetate to the pediatric patient by subcutaneous injection once every 6 months until the patient achieves an age typically associated with the normal onset of puberty, and if suppression is not confirmed, discontinuing administration,
• wherein the release of leuprolide acetate from the in situ solid depot following administration of an initial and subsequent dose provides in a group of pediatric patients having a mean age of 7.5 years at the start of treatment an initial burst of release of leuprolide acetate after the first dose which peaks at 4 hours post dose administration with a mean maximum serum leuprolide concentration of 215.7 ng/ml followed by a plateau phase extending from week 4 to week 48 wherein the release of leuprolide acetate is maintained at a continuous level ranging from 0.18 ng/ml to 0.63 ng/ml with a mean of 0.37 ng/ml,
• wherein the method provides
• (a) a suppression of peak stimulated LH concentrations to less than 4 IU/L after 12 months treatment in more than 80% of pediatric patients being treated,
• (b) a decrease in growth velocity up to about more than 20% over about a 12 month period of treatment in more than about 50% of pediatric patients,
• (c) a suppression of estradiol levels to less than 20 μg/mL in approximately 95% or more of pediatric female patients after 12 months treatment, and
• (d) a suppression of testosterone levels to less than 28.4 ng/dL in approximately 100% of pediatric male patients after 9 months treatment.