Burosumab is a recombinant human monoclonal antibody (IgG1) that binds to and inhibits the activity of fibroblast growth factor 23 (FGF23). By inhibiting FGF23, burosumab increases tubular reabsorption of phosphate from the kidney and increases serum concentration of 1,25 dihydroxy-Vitamin D.
Burosumab absorption from subcutaneous injection sites to blood circulation is nearly complete. Following subcutaneous administration, the median time to reach maximum serum concentrations (Tmax) of burosumab is approximately 7-13 days. The peak serum concentration (Cmax) and area under the concentration-time curve (AUC) of serum burosumab is dose proportional over the dose range of 0.1-2.0 mg/kg.
In XLH patients, the observed volume of distribution of burosumab approximates the volume of plasma, suggesting limited extravascular distribution.
Burosumab is composed solely of amino acids and carbohydrates as a native immunoglobulin and is unlikely to be eliminated via hepatic metabolic mechanisms. Its metabolism and elimination are expected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptides and individual amino acids.
Due to its molecular size, burosumab is not expected to be directly excreted. The clearance of burosumab is dependent on body weight and estimated to be 0.290 L/day and 0.136 L/day in a typical adult (70 kg) and paediatric (30 kg) XLH patient, respectively, with corresponding disposition half-life (t1/2) in the serum ranging from approximately 16 to 19 days. Given the t1/2 estimates, the estimated time to reach the plateau of steady-state exposures is approximately 67 days. Following multiple dose administration to paediatric subjects, observed serum trough concentrations reach a plateau by 8 weeks after initiation of treatment.
Burosumab displays time-invariant pharmacokinetics that is linear to dose over the subcutaneous dose range of 0.1 to 2.0 mg/kg.
With the subcutaneous route of administration, in XLH and TIO subjects, a direct PK-PD relationship between serum burosumab concentrations and increases in serum phosphate concentration is observed and well described by an Emax/EC50 model. Serum burosumab and phosphate concentrations, as well as TmP/GFR, increased and decreased in parallel and reached maximum levels at approximately the same time point after each dose, supporting a direct PK-PD relationship. The AUC for the change from baseline in serum phosphate, TmP/GFR and 1,25(OH)2D increased linearly with increasing burosumab AUC.
No significant difference has been observed in paediatric patient pharmacokinetics or pharmacodynamics as compared with PK/PD in the adult population. Burosumab clearance and volume of distribution are body weight dependent.
The starting dose of burosumab for paediatric patients with TIO is based on Population PK/PD modeling and simulations which indicate that a starting dose of 0.4 mg/kg every 2 weeks for children 25 aged 1-12 years and 0.3 mg/kg every 2 weeks for adolescents aged 13-17 years is predicted to result in a proportion of paediatric patients with TIO reaching normal serum phosphate levels. These can be titrated up to a maximum of 2.0 mg/kg every 2 weeks (the highest dose simulated).
Population PK analyses using data from paediatric and adult subjects who have XLH and adult subjects with TIO indicated that age, sex, race, ethnicity, baseline serum albumin, baseline serum alkaline phosphate, baseline serum alanine aminotransferase, and baseline creatinine clearance ≥49.9 mL/min, were not significant predictors of burosumab PK. Based on the population PK analysis, the PK characteristics of burosumab were similar between XLH and TIO patients.
The effect of burosumab on serum phosphate and calcium levels after food was investigated in two sub-studies (Study UX023-CL301 and UX023-CL303); 13 paediatric patients (aged >3 years) and 26 adult patients (aged 24-65 years). Serum phosphate and calcium were measured at the end of the treatment interval in paediatric patients and mid-interval in adults. Blood samples were taken after a period of fasting, and again 1-2 hours after a standardised meal.
Burosumab treatment did not cause post-prandial excursions above the age-adjusted upper limits of normal in serum phosphate or serum calcium in any paediatric or adult subject in the sub-studies.
Adverse reactions in non-clinical studies with normal animals were observed at exposures which resulted in serum phosphate concentration greater than normal limits. These effects were consistent with an exaggerated response to the inhibition of normal FGF23 levels resulting in a supraphysiologic increase in serum phosphate beyond the upper limit of normal.
Studies in rabbits and adult and juvenile cynomolgus monkeys demonstrated dose-dependent elevations of serum phosphate and 1,25 (OH)2D confirming the pharmacologic actions of burosumab in these species. Ectopic mineralisation of multiple tissues and organs (e.g. kidney, heart, lung, and aorta), and associated secondary consequences (e.g. nephrocalcinosis) in some cases, due to hyperphosphataemia, was observed in normal animals at doses of burosumab that resulted in serum phosphate concentrations in animals greater than approximately 8 mg/dL (2.6 mmol/L). In a murine model of XLH, a significant reduction in the incidence of ectopic mineralisation was observed at equivalent levels of serum phosphate, suggesting that the risk of mineralisation is less in the presence of excess FGF23.
Bone effects seen in adult and juvenile monkeys included changes in bone metabolism markers, increases in thickness and density of cortical bone, increased density of total bone and thickening of long bone. These changes were a consequence of higher than normal serum phosphate levels, which accelerated bone turnover and also led to periosteal hyperostosis and a decrease in bone strength in adult animals, but not in juvenile animals at the doses tested. Burosumab did not promote abnormal bone development, as no changes in femur length or bone strength were noted in juvenile animals. Bone changes were consistent with the pharmacology of burosumab and the role of phosphate in bone mineralization, metabolism and turnover.
In repeat-dose toxicology studies of up to 40 weeks duration in cynomolgus monkeys, mineralisation of the rete testis/seminiferous tubules was observed in male monkeys; however, no changes were observed in semen analysis. No adverse effects on female reproductive organs were observed in these studies.
In the reproductive and developmental toxicology study performed in pregnant cynomolgus monkeys, moderate mineralisation of the placenta was seen in pregnant animals given 30 mg/kg of burosumab and occurred in animals with peak serum phosphate concentration greater than approximately 8 mg/dL (2.6 mmol/L). Shortening of the gestation period and associated increased incidence of premature births were observed in pregnant monkeys at doses of ≥0.3 mg/kg which corresponded to burosumab exposures that are ≥0.875- to 1.39-fold anticipated clinical levels. Burosumab was detected in serum from fetuses indicating that burosumab was transported across the placenta to the fetus. There was no evidence of teratogenic effects. Ectopic mineralisation was not observed in foetuses or offspring and burosumab did not affect pre- and postnatal growth including survivability of the offspring.
In preclinical studies, ectopic mineralisation has been observed in normal animals, most frequently in the kidney, given burosumab at doses that resulted in serum phosphate concentrations greater than 8 mg/dL (2.6 mmol/L). Neither new or clinically meaningful worsening of nephrocalcinosis nor ectopic mineralisation have been observed in clinical trials of patients with XLH treated with burosumab to achieve normal serum phosphate levels.
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