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. 2024 May;63(5):707-719.
doi: 10.1007/s40262-024-01371-6. Epub 2024 Apr 23.

Development of a Weight-Band Dosing Approach for Vosoritide in Children with Achondroplasia Using a Population Pharmacokinetic Model

Yulan Qi  1 , Ming Liang Chan  2 , Diane R Mould  3 , Kevin Larimore  2 , Elena Fisheleva  2 , Anu Cherukuri  2 , Jonathan Day  4 , Ravi Savarirayan  5 , Melita Irving  6 , Carlos A Bacino  7 , Julie Hoover-Fong  8 , Keiichi Ozono  9 , Klaus Mohnike  10 , William R Wilcox  11 , Michael B Bober  12 , Joshua Henshaw  2
Affiliations

Development of a Weight-Band Dosing Approach for Vosoritide in Children with Achondroplasia Using a Population Pharmacokinetic Model

Yulan Qi et al. Clin Pharmacokinet. 2024 May.

Abstract

Background and objective: Vosoritide is a recently approved therapy for achondroplasia, the most common form of disproportionate short stature, that has been shown to be well tolerated and effective in increasing linear growth. This study aimed to develop a population pharmacokinetic (PPK) model to characterize pharmacokinetics (PK) of vosoritide and establish a weight-band dosing regimen.

Methods: A PPK model was developed using data from five clinical trials in children with achondroplasia (aged 0.95-15 years) who received daily per-kg doses of vosoritide. The model was used to simulate expected exposures in children with a refined weight-band dosing regimen. Simulated exposure was compared with the observed exposure from the pivotal clinical trial to evaluate appropriateness of the weight-band dosing regimen.

Results: A one-compartment model with a change-point first-order absorption and first-order elimination accurately described PK of vosoritide in children with achondroplasia. Body weight was found to be a predictor of vosoritide's clearance and volume of distribution. Additionally, it was observed that dosing solution concentration and duration of treatment influenced bioavailability. The weight-band dosing regimen resulted in simulated exposures that were within the range demonstrated to be well tolerated and effective in the pivotal clinical trial and showed improved consistency in drug exposure across the achondroplasia population.

Conclusions: The weight-band dosing regimen reduced the number of recommended dose levels by body weight and is expected to simplify dosing for children with achondroplasia and their caregivers.

Clinical trial registration: NCT02055157, NCT02724228, NCT03197766, NCT03424018, and NCT03583697.

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Conflict of interest statement

Y.Q., K.L., E.F., A.C., J.D., and J.H.: employees and shareholders of BioMarin Pharmaceutical Inc. M.L.C.: former employee and stockholder of BioMarin Pharmaceutical Inc. D.R.M.: paid consultant for BioMarin Pharmaceutical Inc. R.S. and K.O.: honoraria from BioMarin Pharmaceutical Inc. M.I.: honoraria for consultancy services relating to the subject of this manuscript. C.A.B. and K.M.: no conflicts of interest. J.H.-.F.: institution received funding from BioMarin Pharmaceutical Inc. to execute the study presented in this manuscript. Funds were also received from Pfizer and QED for other achondroplasia-related studies. J.H.-F.: consultant for BioMarin Pharmaceutical Inc., Pfizer, QED, and Sanofi, related to achondroplasia. W.R.W.: local principal investigator for the vosoritide studies at Emory University, funded by a clinical trial contract from BioMarin Pharmaceutical Inc. to Emory University. W.R.W. received honoraria for advisory committee meetings from BioMarin Pharmaceutical Inc. BioMarin Pharmaceutical Inc. paid for writing assistance for the manuscript. M.B.B.: employed by the Nemours Foundation, which has received institutional support for research from Ascendis Pharma, BioMarin Pharmaceutical Inc., QED, and Therachon/Pfizer. His institution has received consulting fees from BioMarin Pharmaceutical Inc. and Tyra Biosciences. M.B.B. has received consulting fees from Ascendis Pharma, BioMarin Pharmaceutical Inc., QED, and Therachon/Pfizer. He has received compensation for speaking on behalf of the Alexion speaker’s bureau and from Novo Nordisk and Tyra Biosciences. In the future, he will be employed by Tyra Biosciences.

Figures

Fig. 1
Fig. 1
Goodness of fit of the final PPK model. Basic goodness-of-fit plots are provided. Open blue symbols represent studies 111-202 and 111-205, study 111-206 is represented with open red symbols, and studies 111-301 and 111-302 are represented with filled blue symbols. Concentration is given in µg/L, the solid gray line is the line of unity or identity as appropriate, and the dashed black line is a loess smooth. PPK population pharmacokinetics
Fig. 2
Fig. 2
Dose-normalized VPC results for the PPK model; dose-normalized observed and simulated vosoritide concentrations versus time after first dose. Dose-normalized VPC simulated with the PPK model and dose-normalized observed versus time after first dose are presented. Observed data are represented with black open circles, the median of the observed data is represented by a solid black line, the dashed lines are the upper and lower 90th percentiles of the observed data, the red area is the 90% confidence interval of the median of the simulated data, and the purple shaded areas are the 90% confidence intervals of the upper and lower 90th percentiles of the simulated data. PPK population pharmacokinetics, VPC visual predictive check
Fig. 3
Fig. 3
Simulated vosoritide AUC values compared with observed AUC values at 15 μg/kg from study 111-301. The median simulated exposure metrics for each weight are represented by the black squares, the upper and lower whiskers represent the lower 5th and upper 95th percentiles of exposure, the lower 5th and upper 95th percentiles of observed metrics from the comparison study are represented by red dashed lines, and the red solid line represents the median. AUC area under the plasma concentration–time curve
Fig. 4
Fig. 4
Simulated vosoritide Cmax values compared with observed Cmax values at 15 μg/kg from study 111-301. The median simulated exposure metrics for each weight are represented by the black squares, the upper and lower whiskers represent the lower 5th and upper 95th percentiles of exposure, the lower 5th and upper 95th percentiles of observed metrics from the comparison study are represented by red dashed lines, and the red solid line represents the median. Cmax maximum observed plasma concentration
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