In Vitro–In Vivo Correlation on Delivery of Drug Candidates to Articular Cartilage

Abstract

A correlation in cartilage drug concentration was observed between in vitro and in vivo studies. Plasma protein binding and the test article's affinity to cartilage were the major determining factors for drug delivery to cartilage in vivo.

Plasma protein binding: From discovery to development

“…PPB optimization, based on thorough PK/PD assessment has been efficiently demonstrated in the case of matrix metalloprotease (MMP‐13) inhibitors 37. Robust in vitro – in vivo correlation (IVIVC), linking plasma and synovial fluid (SF) drug levels were first established that suggested crucial role of PPB and cartilage accumulation in vitro , in the cartilage delivery of compounds in vivo .…”

Suppression of cathepsin K biomarker in synovial fluid as a free-drug–driven process

“…protein binding of >98%), drug concentration in synovial fluid in reference to that in plasma should be proportional to the (albumin) protein concentration ratio between these two matrices—an observation that was reported for inhibitors of matrix metalloprotease following oral administration of compound to rabbits. 11 With the consideration of a 2.8-fold difference in protein content between synovial fluid and plasma, drug binding to synovial fluid can be estimated from the plasma protein binding value determined in vitro. 13 This approach allows a projection of drug concentration in synovial fluid based on plasma drug level when equilibrium of unbound drug is reached between these matrices.…”

“…For cartilage harvested from knee joint of dog and rabbit, each milligram of tissue was enzymatically digested with 4 µL of phosphate-buffered saline containing 2 mg/mL each of collagenase (Wako Chemicals, Richmond, Virginia, USA) and hyaluronidase at 37°C for 24 h and then processed with a protein precipitation method followed by LC-MS/MS analysis. Binding of MK-1256 to plasma proteins and to cartilage were performed as described by Ma et al 10 and Wang et al, 11 respectively.…”

“…in which the fraction unbound of MK-1256 in synovial fluid was calculated based on a 2.8-fold difference in protein content between synovial fluid (approximately 25 mg/mL) and plasma (approximately 69 mg/mL), 11 –13 and the cartilage binding factor was determined by incubation of MK-1256 with bovine knee cartilage based on the method previously reported. 11 Statistical analyses, including Student’s t -test, were performed using the Microsoft Excel software package (Redmond, Washington, USA).…”

Advances in the development of novel aggrecanase inhibitors

“…They concluded that the more hydrophilic the compound, the greater the permeability. More recently, researchers a Wyeth looked at the effect of serum albumin on cartilage concentrations obtained in a cartilage explant assay [36]. They found that in the absence of albumin, compounds with a smaller fraction unbound to plasma protein show higher cartilage penetration.…”