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Therapeutic Class: KEYTRUDA (pembrolizumab) is an antineoplastic agent, monoclonal antibody.
PHARMACOLOGY: Mechanism of Action: PD-1 is an immune-checkpoint receptor that limits the activity of T lymphocytes in peripheral tissues. The PD-1 pathway is an immune control checkpoint that may be engaged by tumor cells to inhibit active T-cell immune surveillance. KEYTRUDA is a high affinity antibody against PD-1, which exerts dual ligand blockade of the PD-1 pathway, including PD-L1 and PD-L2, on antigen presenting or tumor cells. By inhibiting the PD-1 receptor from binding to its ligands, KEYTRUDA reactivates tumor-specific cytotoxic T lymphocytes in the tumor microenvironment and reactivates anti-tumor immunity.
The anti-angiogenic effect of lenvatinib (multi-TKI) in combination with the immune-stimulatory effect of pembrolizumab (anti-PD-1) results in a tumor microenvironment with greater T-cell activation to help overcome primary and acquired resistance to immunotherapy and may improve tumor responses compared to either treatment alone.
In preclinical murine models, PD-1 plus TKI inhibitors have demonstrated enhanced anti-tumor activity compared to either agent alone.
Pharmacodynamics: Based on the modeling of dose/exposure relationships for efficacy and safety for pembrolizumab, there are no clinically significant differences in efficacy and safety between the doses of 200 mg or 2 mg/kg every 3 weeks or 400 mg every 6 weeks.
In peripheral blood of patients who received KEYTRUDA 2 mg/kg every 3 weeks or 10 mg/kg every 2 weeks or 3 weeks, an increased percentage of activated (i.e., HLA-DR+) CD4+ and CD8+ T-cells was observed after treatment at all doses and schedules without an increase in the circulating T-lymphocyte number.
Pharmacokinetics: The pharmacokinetics of pembrolizumab was studied in 2993 patients with various cancers who received doses in the range of 1 to 10 mg/kg every 2 weeks, 2 to 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. There are no clinically meaningful differences in pharmacokinetics of pembrolizumab across indications.
Absorption: KEYTRUDA is dosed via the IV route and therefore is immediately and completely bioavailable.
Distribution: Consistent with a limited extravascular distribution, the volume of distribution of pembrolizumab at steady state is small (6.0 L; coefficient of variation [CV]: 20%). As expected for an antibody, pembrolizumab does not bind to plasma proteins in a specific manner.
Metabolism: Pembrolizumab is catabolized through non-specific pathways; metabolism does not contribute to its clearance.
Elimination: Pembrolizumab clearance (CV%) is approximately 23% lower [geometric mean, 195 mL/day (40%)] after achieving maximal change at steady state compared with the first dose (252 mL/day [CV%: 37%]); this decrease in clearance with time is not considered clinically important. The geometric mean value (CV%) for the terminal half-life (t½) is 22 days (32%).
Steady-state concentrations of pembrolizumab were reached by 16 weeks of repeated dosing with an every 3-week regimen and the systemic accumulation was 2.1-fold. The peak concentration (Cmax), trough concentration (Cmin), and area under the plasma concentration versus time curve at steady state (AUCss) of pembrolizumab increased dose proportionally in the dose range of 2 to 10 mg/kg every 3 weeks.
Special Populations: The effects of various covariates on the pharmacokinetics of pembrolizumab were assessed in population pharmacokinetic analyses. The following factors had no clinically important effect on the clearance of pembrolizumab: age (range 15-94 years), gender, race, mild or moderate renal impairment, mild or moderate hepatic impairment, and tumor burden. The relationship between body weight and clearance supports the use of either fixed dose or body weight-based dosing to provide adequate and similar control of exposure. Pembrolizumab concentrations with weight-based dosing at 2 mg/kg every 3 weeks in pediatric patients (2 to 17 years) are comparable to those of adults at the same dose.
Renal Impairment: The effect of renal impairment on the clearance of pembrolizumab was evaluated by population pharmacokinetic analysis in patients with mild (GFR <90 and ≥60 mL/min/1.73 m2) or moderate (GFR <60 and ≥30 mL/min/1.73 m2) renal impairment compared to patients with normal (GFR ≥90 mL/min/1.73 m2) renal function. No clinically important differences in the clearance of pembrolizumab were found between patients with mild or moderate renal impairment and patients with normal renal function. KEYTRUDA has not been studied in patients with severe (GFR <30 and ≥15 mL/min/1.73 m2) renal impairment. [See Renal Impairment under DOSAGE & ADMINISTRATION.]
Hepatic Impairment: The effect of hepatic impairment on the clearance of pembrolizumab was evaluated by population pharmacokinetic analysis in patients with mild and moderate hepatic impairment (total bilirubin (TB) 1.0 to 1.5 x ULN or AST >ULN and TB >1.5 to 3 x ULN and any AST, respectively, as defined using the National Cancer Institute criteria of hepatic dysfunction) compared to patients with normal hepatic function (TB and AST ≤ULN). No clinically important differences in the clearance of pembrolizumab were found between patients with mild or moderate hepatic impairment and normal hepatic function. KEYTRUDA has not been studied in patients with severe (TB >3 x ULN and any AST) hepatic impairment. [See Hepatic Impairment under DOSAGE & ADMINISTRATION.]
