BACKGROUND AND OBJECTIVE: Thyroid eye disease (TED) is characterized by inflammation/expansion of orbital tissues, proptosis, and diplopia. Teprotumumab is the first US Food and Drug Administration-approved therapy for TED, administered as an initial intravenous infusion of 10 mg/kg followed by 20 mg/kg every 3 weeks for an additional seven infusions. The objective of this article is to discuss the pharmacokinetics and exposure-response profile for teprotumumab in patients with TED. METHODS: A population pharmacokinetic analysis was performed to characterize pharmacokinetics and select dosing in patients with TED. Exposure-response was evaluated for efficacy (proptosis response, clinical activity score categorical response, and diplopia response) and safety (hyperglycemia, muscle spasms, and hearing impairment) parameters. RESULTS: Teprotumumab pharmacokinetics was linear in patients with TED, with low systemic clearance (0.334 L/day), low volume of distribution (3.9 and 4.2 L for the central and peripheral compartment, respectively), and a long elimination half-life (19.9 days). The approved dosing regimen provided > 20 µg/mL for > 90% insulin-like growth factor 1 receptor saturation throughout the dosing interval. Model-predicted mean (± standard deviation) steady-state area under the concentration-time curve, peak, and trough concentrations in patients with TED were 131 (± 30.9) mg∙h/mL, 643 (± 130) µg/mL, and 157 (± 50.6) µg/mL, respectively. Female patients had a 15% higher steady-state peak concentration but a similar steady-state area under the concentration-time curve vs male patients. No other covariates affected teprotumumab pharmacokinetics. No meaningful correlations between teprotumumab exposures and efficacy or safety parameters were observed. CONCLUSIONS: Teprotumumab pharmacokinetics was well characterized in patients with TED, and generally consistent with other IgG1 antibodies. Efficacy was consistent across the exposure range with a well-tolerated safety profile supporting the current dose regimen for patients with TED.
BACKGROUND AND OBJECTIVE:Thyroid eye disease (TED) is characterized by inflammation/expansion of orbital tissues, proptosis, and diplopia. Teprotumumab is the first US Food and Drug Administration-approved therapy for TED, administered as an initial intravenous infusion of 10 mg/kg followed by 20 mg/kg every 3 weeks for an additional seven infusions. The objective of this article is to discuss the pharmacokinetics and exposure-response profile for teprotumumab in patients with TED. METHODS: A population pharmacokinetic analysis was performed to characterize pharmacokinetics and select dosing in patients with TED. Exposure-response was evaluated for efficacy (proptosis response, clinical activity score categorical response, and diplopia response) and safety (hyperglycemia, muscle spasms, and hearing impairment) parameters. RESULTS:Teprotumumab pharmacokinetics was linear in patients with TED, with low systemic clearance (0.334 L/day), low volume of distribution (3.9 and 4.2 L for the central and peripheral compartment, respectively), and a long elimination half-life (19.9 days). The approved dosing regimen provided > 20 µg/mL for > 90% insulin-like growth factor 1 receptor saturation throughout the dosing interval. Model-predicted mean (± standard deviation) steady-state area under the concentration-time curve, peak, and trough concentrations in patients with TED were 131 (± 30.9) mg∙h/mL, 643 (± 130) µg/mL, and 157 (± 50.6) µg/mL, respectively. Female patients had a 15% higher steady-state peak concentration but a similar steady-state area under the concentration-time curve vs male patients. No other covariates affected teprotumumab pharmacokinetics. No meaningful correlations between teprotumumab exposures and efficacy or safety parameters were observed. CONCLUSIONS:Teprotumumab pharmacokinetics was well characterized in patients with TED, and generally consistent with other IgG1 antibodies. Efficacy was consistent across the exposure range with a well-tolerated safety profile supporting the current dose regimen for patients with TED.
Authors: Terry J Smith; George J Kahaly; Daniel G Ezra; James C Fleming; Roger A Dailey; Rosa A Tang; Gerald J Harris; Alessandro Antonelli; Mario Salvi; Robert A Goldberg; James W Gigantelli; Steven M Couch; Erin M Shriver; Brent R Hayek; Eric M Hink; Richard M Woodward; Kathleen Gabriel; Guido Magni; Raymond S Douglas Journal: N Engl J Med Date: 2017-05-04 Impact factor: 91.245
Authors: Shanli Tsui; Vibha Naik; Neil Hoa; Catherine J Hwang; Nikoo F Afifiyan; Amiya Sinha Hikim; Andrew G Gianoukakis; Raymond S Douglas; Terry J Smith Journal: J Immunol Date: 2008-09-15 Impact factor: 5.422
Authors: Raymond S Douglas; Vibharavi Naik; Catherine J Hwang; Nikoo F Afifiyan; Andrew G Gianoukakis; Daniel Sand; Shweta Kamat; Terry J Smith Journal: J Immunol Date: 2008-10-15 Impact factor: 5.422
Authors: Raymond S Douglas; George J Kahaly; Amy Patel; Saba Sile; Elizabeth H Z Thompson; Renee Perdok; James C Fleming; Brian T Fowler; Claudio Marcocci; Michele Marinò; Alessandro Antonelli; Roger Dailey; Gerald J Harris; Anja Eckstein; Jade Schiffman; Rosa Tang; Christine Nelson; Mario Salvi; Sara Wester; Jeffrey W Sherman; Thomas Vescio; Robert J Holt; Terry J Smith Journal: N Engl J Med Date: 2020-01-23 Impact factor: 91.245