A semimechanistic and mechanistic population PK–PD model for biomarker response to ibandronate, a new bisphosphonate for the treatment of osteoporosis

Abstract

AimsIbandronate, a highly potent nitrogen-containing bisphosphonate, is the subject of an ongoing clinical development programme that aims to maximize the potential of simplified, less frequent oral and intravenous (i.v.) administration in osteoporosis. A modelling and simulation project was undertaken to characterize further the clinical pharmacology of ibandronate and identify convenient intermittent oral and i.v. regimens for clinical evaluation. Methods and resultsUsing selected data from clinical studies involving 174 women with postmenopausal osteoporosis (PMO), a classical multicompartmental pharmacokinetic-pharmacodynamic (PK-PD) model was developed that accurately described the P K of i.v. ibandronate in plasma and urine and urinary excretion of the C-telopeptide of the a chain of type I collagen (uCTX), a sensitive biomarker of PD response to ibandronate. To reduce processing times, the classical PK-PD model was simplified using a 'kinetics of drug action' or kinetic (K)-PD model (i.e. a dose-response model as opposed to a dose-concentration-response model). The performance of the K-PD model was evaluated by fitting data simulated with the PK-PD model under various dosing regimens. The simplified model produced a virtually indistinguishable fit of the data from that of the PK-PD model. The K-PD model was extended to consider the influence of supplemental therapy (calcium with or without vitamin D) on the P D response and validated by retrospectively simulating the uCT X response in a prior Phase III and Phase II/III study of i.v. ibandronate, given once every 3 months, in 3380 women with PMO. The observed median uCTX responses at the scheduled assessment points in the completed studies were within the distribution of the simulated responses. The K-PD model for i.v. ibandronate was extended further to allow simultaneous fitting of uCTX responses after i.v. and oral administration in 676 postmenopausal women with osteoporosis, and validated by retrospectively simulating the data observed in a Phase I study of oral daily ibandronate in 180 women with PMO. The K-PD model adequately described the uCTX response after oral dosing. ConclusionsThis validated K-PD model is currently being used to evaluate a range of novel intermittent oral and i.v. ibandronate regimens in an ongoing clinical development programme.

Modeling Corticosteroid Effects in a Rat Model of Rheumatoid Arthritis I: Mechanistic Disease Progression Model for the Time Course of Collagen-Induced Arthritis in Lewis Rats

“…Post and Danhof presented a variety of equations for describing disease progression using pharmacodynamic indirect response models, a mechanistic paradigm for describing turnover of response and drug effect (Dayneka et al, 1993;Post et al, 2005). Other diseases have been described, including bacterial cell growth and irreversible loss after drug therapy, fasting plasma glucose in diabetes, and pain and bone mineral density progression in osteoarthritis (Jusko, 1971;Ravn et al, 1996;Meunier et al, 1999;Frey et al, 2003;Pillai et al, 2004;de Winter et al, 2006). Mechanism-based disease progression models are continually being derived because their insight into how various pathologies contribute to progression and how drugs exert their effects on specific processes is essential to optimizing therapy (Holford and Peace, 1992a,b;Nemeroff, 1994;Hoogendoorn et al, 2005;Holford et al, 2006;Meier et al, 2007;Woo et al, 2008).…”

Dissociated Agonist of Glucocorticoid Receptor or Prednisone for Active Rheumatoid Arthritis: Effects on P1NP and Osteocalcin Pharmacodynamics

“…Application of the K‐PD approach in clinical trials has been reported to sufficiently describe the time course of PD data in the absence of drug concentration measurements 12, 13, 14, 15. A bone biomarker analysis in urine (bone resorption marker urine C‐terminal telopeptide in osteoporosis treatment with bisphosphonate) used a similar approach to our biomarker analysis, with a K‐PD model 16. They evaluated drug regimens in ongoing clinical development with both K‐PD and pharmacokinetic (PK)‐PD models and concluded that the K‐PD model adequately described the biomarker response.…”

Dose–response-time modelling: Second-generation turnover model with integral feedback control

“…Since the work of Smolen, DRT data analysis has been proven to be applicable to novel sys- 20 tems where the kinetics and/or dynamics behave non-linearly, when there are time-delays in the response data, and when the system contains feedback mechanisms [24]. The technique has successfully been applied in models of the muscle relaxant drug vecuronium [14,22,21,64], antinociceptive drugs [1,26,24], ophthalmic drugs [24,41], antidepressants [28], psycho-motor stimulants [26], drugs 25 to treat chronic obstructive pulmonary disease (COPD) [65], and osteoporosis [46]. For a review and theoretical guide to DRT analysis see Gabrielsson et al.…”

“…[24,26]. DRT models go under the name of K-PD (K for kinetic) models in some analyses [28,29,35,46,65]. However, in the latter case the biophase turnover rate, rather than the biophase amount, is driving the response.…”