Cobimetinib is a MEK inhibitor currently in clinical trials as an anticancer agent. The objectives of this study were to determine in vitro and in vivo if cobimetinib is a substrate of P-glycoprotein ...(P-gp) and/or breast cancer resistance protein (Bcrp1) and to assess the implications of efflux on cobimetinib pharmacokinetics (PK), brain penetration, and target modulation. Cell lines transfected with P-gp or Bcrp1 established that cobimetinib was a substrate of P-gp but not a substrate of Bcrp1. In vivo, after intravenous and oral administration of cobimetinib to FVB (wild-type; WT), Mdr1a/b(−/−), Bcrp1 (−/−), and Mdr1a/b(−/−)/Bcrp(−/−) knockout (KO) mice, clearance was similar in WT (35.5 ± 16.7 mL/min/kg) and KO animals (22.0 ± 3.6 to 27.6 ± 5.2 mL/min/kg); oral exposure was also similar between WT and KO animals. After an oral 10 mg/kg dose of cobimetinib, the mean total brain to plasma ratio (Kp) at 6 h postdose was 0.3 and 0.2 in WT and Bcrp1(−/−) mice, respectively. In Mdr1a/b(−/−) and Mdr1a/1b/Bcrp1(−/−) KO mice and WT mice treated with elacridar (a P-gp and BCRP inhibitor), Kp increased to 11, 6, and 7, respectively. Increased brain exposure in Mdr1a/b(−/−) and Mdr1a/1b/Bcrp1(−/−) KO and elacridar treated mice was accompanied by up to ∼65% suppression of the target (pErk) in brain tissue, compared to WT mice. By MALDI imaging, the cobimetinib signal intensity was relatively high and was dispersed throughout the brain of Mdr1a/1b/Bcrp1(−/−) KO mice compared to low/undetectable signal intensity in WT mice. The efflux of cobimetinib by P-gp may have implications for the treatment of patients with brain tumors/metastases.
Purpose: To determine whether there was a difference in the sensitivity to change of the subscales of the Functional Independence Measure and the Assessment of Motor and Process Skills within three ...different post-acute inpatient rehabilitation populations.
Material and methods: We conducted retrospective chart review of patients consecutively admitted to inpatient rehabilitation units, with both admission and discharge Functional Independence Measure and Assessment of Motor and Process Skills scores. A total of 276 participants were included and categorized into diagnostic groups (orthopedic, oncology, and geriatric). Within group, sensitivity to change was evaluated for the subscales of each measure by calculating the difference in standardized response means (SRM) and 95% confidence intervals (CI).
Results: The Functional Independence Measure motor subscale was more sensitive to change than the Assessment of Motor and Process Skills in the orthopedic and geriatric groups (SRM
difference
= 1.53 95% CI 0.93, 2.3 and 0.65 95% CI 0.3, 1.02, respectively) but not in the oncology group (SRM
difference
= 0.42 95% CI −0.2, 1.04). For the cognitive subscales, the Assessment of Motor and Process Skills was more sensitive to change than the Functional Independence Measure in all three groups (SRM
difference
= 0.38 95% CI 004, 0.74, 0.65 95% CI 0.45, 0.90, and 1.15 95% CI 0.77, 1.69 for orthopedic, geriatric, and oncology, respectively).
Conclusions: The Functional Independence Measure is a mandated measure for all rehabilitation units in Canada. As the cognitive subscale of the Assessment of Motor and Process Skills is more sensitive to change than the Functional Independence Measure, we recommend also administering the Assessment of Motor and Process Skills to better detect changes in the cognitive aspect of function.
Implications for rehabilitation
When deciding between the Functional Independence Measure or the Assessment of Motor and Process Skills, it is important to consider whether patients' functional status is expected to change similarly or differently.
The difference in sensitivity to change between the subscales of the two outcome measures varies with the characteristics of change (similar or different) in patients' functional status.
We recommend using the Assessment of Motor and Process Skills, along with the Functional Independence Measure, for patients who are expected to make similar amounts of change in functional status, as the cognitive subscale of the Assessment of Motor and Process Skills is more sensitive to change and can better detect changes in the cognitive aspect of functioning.
For patients whose functional status are expected to change differently (diverse diagnoses), the Functional Independence Measure may be more useful as the motor subscale was more sensitive to change when comparing between rehabilitation populations.
