Simple model to explain effects of plasma protein binding and tissue binding on calculated volumes of distribution, apparent elimination rate constants and clearances

A simple pharmacokinetic model, incorporating linear plasma protein binding, linear tissue binding, and first order elimination of free (unbound) drug, was studied. If Cl p is the plasma clearance, V f is the “true” volume of distribution of free drug, β is the apparent elimination rate constant, σ is the fraction of the drug which is free in plasma, f is the fraction of the drug which is free in the entire body, k f is the intrinsic elimination rate constant for free drug, and A TB o is the initial amount of drug which is bound to tissues, then the model indicates that the following relationships hold: (1) Cl p = V f σ k f ; (2) β = f k f ; and V dext = (σ/f) V f . Only σ, and not f, can be measured experimentally . Dividing Cl p by σ provides an estimate of the intrinsic clearance of free drug, V f k f . A plot of V dext versus σ has an intercept equal to V f , and the ratio of the slope/intercept is an estimate of A TB o /A f o , where A f o is the initial amount of free drug (equal to V f times initial concentration of free drug in plasma). Thus, an estimate of A TB o may be obtained. Dividing the intrinsic clearance by V f provides an estimate of k f . Thus, theoretically, estimates of V f , k f , A TB o and f may be obtained. The variables are not separated when β is plotted versus σ, and curvature of such plots is expected; no useful information is obtained from such plots.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46634/1/228_2004_Article_BF00563079.pd

Burosumab treatment in adults with X-linked hypophosphataemia: 96-week patient-reported outcomes and ambulatory function from a randomised phase 3 trial and open-label extension

Objectives To report the impact of burosumab on patient-reported outcomes (PROs) and ambulatory function in adults with X-linked hypophosphataemia (XLH) through 96 weeks. Methods Adults diagnosed with XLH were randomised 1:1 in a double-blinded trial to receive subcutaneous burosumab 1 mg/kg or placebo every 4 weeks for 24 weeks (NCT02526160). Thereafter, all subjects received burosumab every 4 weeks until week 96. PROs were measured using the Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC), Brief Pain Inventory-Short Form (BPI-SF) and Brief Fatigue Inventory (BFI), and ambulatory function was measured with the 6 min walk test (6MWT). Results Subjects (N=134) were randomised to burosumab (n=68) or placebo (n=66) for 24 weeks. At baseline, subjects experienced pain, stiffness, and impaired physical and ambulatory function. At week 24, subjects receiving burosumab achieved statistically significant improvement in some BPI-SF scores, BFI worst fatigue (average and greatest) and WOMAC stiffness. At week 48, all WOMAC and BPI-SF scores achieved statistically significant improvement, with some WOMAC and BFI scores achieving meaningful and significant change from baseline. At week 96, all WOMAC, BPI-SF and BFI achieved statistically significant improvement, with selected scores in all measures also achieving meaningful change. Improvement in 6MWT distance and percent predicted were statistically significant at all time points from 24 weeks. Conclusions Adults with XLH have substantial burden of disease as assessed by PROs and 6MWT. Burosumab treatment improved phosphate homoeostasis and was associated with a steady and consistent improvement in PROs and ambulatory function. Trial registration number NCT02526160

Fibrodysplasia ossificans progressiva: what have we achieved and where are we now?: Follow-up to the 2015 Lorentz workshop

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare progressive genetic disease effecting one in a million individuals. During their life, patients with FOP progressively develop bone in the soft tissues resulting in increasing immobility and early death. A mutation in the ACVR1 gene was identified as the causative mutation of FOP in 2006. After this, the pathophysiology of FOP has been further elucidated through the efforts of research groups worldwide. In 2015, a workshop was held to gather these groups and discuss the new challenges in FOP research. Here we present an overview and update on these topics.Diabetes mellitus: pathophysiological changes and therap