Physiologically‐based pharmacokinetic model for alectinib, ruxolitinib, and panobinostat in the presence of cancer, renal impairment, and hepatic impairment

• Published in: Biopharmaceutics & drug disposition 2021-06, Vol.42 (6), p.263-284
• Main Authors: Alsmadi, Mo'tasem M., AL‐Daoud, Nour M, Jaradat, Mays M., Alzughoul, Saja B., Abu Kwiak, Amani D., Abu Laila, Salam S., Abu Shameh, Ayat J., Alhazabreh, Mohammad K., Jaber, Sana'a A., Abu Kassab, Hala T.
• Format: Article
• Language: English
• Subjects: altered body physiology; Blood flow; Cancer; Cerebrospinal fluid; clinical PK study simulation through PBPK; Ethics; Gastric emptying; Glomerular filtration rate; Hematocrit; hepatic impairment; Liver; Non-small cell lung carcinoma; Pharmacokinetics; Population studies; renal impairment; Targeted cancer therapy; Toxicity
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/bdd.2282

Renal (RIP) and hepatic (HIP) impairments are prevalent conditions in cancer patients. They can cause changes in gastric emptying time, albumin levels, hematocrit, glomerular filtration rate, hepatic functional volume, blood flow rates, and metabolic activity that can modify drug pharmacokinetics. Performing clinical studies in such populations has ethical and practical issues. Using predictive physiologically‐based pharmacokinetic (PBPK) models in the evaluation of the PK of alectinib, ruxolitinib, and panobinostat exposures in the presence of cancer, RIP, and HIP can help in using optimal doses with lower toxicity in these populations. Verified PBPK models were customized under scrutiny to account for the pathophysiological changes induced in these diseases. The PBPK model‐predicted plasma exposures in patients with different health conditions within average 2‐fold error. The PBPK model predicted an area under the curve ratio (AUCR) of 1, and 1.8, for ruxolitinib and panobinostat, respectively, in the presence of severe RIP. On the other hand, the severe HIP was associated with AUCR of 1.4, 2.9, and 1.8 for alectinib, ruxolitinib, and panobinostat, respectively, in agreement with the observed AUCR. Moreover, the PBPK model predicted that alectinib therapeutic cerebrospinal fluid levels are achieved in patients with non‐small cell lung cancer, moderate HIP, and severe HIP at 1‐, 1.5‐, and 1.8‐fold that of healthy subjects. The customized PBPK models showed promising ethical alternatives for simulating clinical studies in patients with cancer, RIP, and HIP. More work is needed to quantify other pathophysiological changes induced by simultaneous affliction by cancer and RIP or HIP. Physiologically‐Based Pharmacokinetic (PBPK) Models were developed, customized, and used to predict the exposures of ruxolitinib, and panobinostat in plasma and that of alectinib in its target site (the cerebrospinal fluid) in patients with cancer, renal impairment, and hepatic impairment. The customized PBPK models showed promising ethical alternative for simulating clinical studies, and provided a theoretical basis for safer drug administration and better therapeutic effects in cancer patients with and without comorbidities.