ALIQOPA - Pharmacology copanlisib

ALIQOPA (copanlisib) is a kinase inhibitor for intravenous infusion. The active pharmaceutical ingredient is copanlisib dihydrochloride which exists as a non-stoichiometric hydrate and has the molecular formula of C₂₃H₂₈N₈O₄ 2HCl and a molecular weight of 553.45 g/mol. The molecular formula and molecular weight are based on the anhydrous form. The chemical name is 2-amino-N-{7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide dihydrochloride. Copanlisib dihydrochloride has the following structural formula:

ALIQOPA is supplied in single-dose vials as a sterile lyophilized solid for reconstitution and further dilution for intravenous infusion. The product is white to slightly yellowish. After reconstitution, the solution is colorless to slightly yellowish. Each vial contains 60 mg copanlisib free base (equivalent to 69.1 mg copanlisib dihydrochloride). After reconstitution, each mL contains 15 mg copanlisib free base (equivalent to 17.3 mg copanlisib dihydrochloride).

Inactive ingredients: Citric acid anhydrous, mannitol, sodium hydroxide.

Copanlisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K-α and PI3K-δ isoforms expressed in malignant B cells. Copanlisib has been shown to induce tumor cell death by apoptosis and inhibition of proliferation of primary malignant B cell lines. Copanlisib inhibits several key cell-signaling pathways, including B-cell receptor (BCR) signaling, CXCR12 mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines.

At 60 mg (or 0.8 mg/kg) of ALIQOPA dose, the elevation of plasma glucose was associated with higher copanlisib exposure.

cardiac electrophysiology

The effect of the recommended ALIQOPA dose of 60 mg on the QTc interval was evaluated in an open label, dedicated QT study of 25 patients with advanced cancer. No large mean QTc prolongation >20 ms above baseline was observed.

The area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C_max) of ALIQOPA increase dose-proportionally over 5 to 93 mg (0.08 to 1.55 times the approved recommended dose) absolute dose range and exhibit linear pharmacokinetics (PK). There is no time-dependency and no accumulation in the PK of copanlisib.

The geometric mean (range) steady state copanlisib exposure at 0.8 mg/kg (approximately the approved recommended dose of 60 mg) are 463 (range: 105 to 1670; SD: 584) ng/mL for C_max and 1570 (range: 536 to 3410; SD: 338) ng.hr/mL for AUC_0-25h.

distribution

The in vitro human plasma protein binding of copanlisib is 84.2%. Albumin is the main binding protein. The in vitro mean blood-to-plasma ratio is 1.7 (range: 1.5 to 2.1). The geometric mean volume of distribution is 871 (range: 423 to 2150; SD: 479) L.

elimination

The geometric mean terminal elimination half-life of copanlisib is 39.1 (range: 14.6 to 82.4; SD: 15.0) hours. The geometric mean clearance is 17.9 (range: 7.3 to 51.4; SD: 8.5) L/hr.

metabolism

Approximately >90% of copanlisib metabolism is mediated by CYP3A and <10% by CYP1A1. The M-1 metabolite accounts for 5% of total radioactivity AUC and its pharmacological activity is comparable to the parent compound copanlisib for the tested kinases PI3KandPI3K.

excretion

Copanlisib is excreted approximately 50% as unchanged compound and 50% as metabolites in humans. Following a single intravenous dose of 12 mg (0.2 times the recommended approved dose) radiolabeled copanlisib, approximately 64% of the administered dose was recovered in feces and 22% in urine within 20 to 34 days. Unchanged copanlisib represented approximately 30% of the administered dose in feces and 15% in urine. Metabolites resulting from CYP450-mediated oxidation metabolism accounted for 41% of the administered dose.

specific populations

Age (20 to 90 years), gender, race (White, Asian, Hispanic, and Black), smoking status, body weight (41 to 130 kg), and mild, moderate, and severe renal impairment [CLcr ≥ 15 mL/min as estimated by Cockcroft-Gault (C-G) equation] had no clinically significant effect on the PK of copanlisib. The PK of copanlisib in patients with end stage renal disease (CLcr < 15 mL/min by C-G equation) with or without dialysis is unknown.

patients with hepatic impairment

Based on a population PK analysis in patients with cancer, mild hepatic impairment [total bilirubin ≤ 1 x ULN and AST > ULN, or total bilirubin < 1-1.5 x ULN and any AST] had no clinically relevant effect on the PK of copanlisib.

In a dedicated PK study evaluating a single intravenous dose of 12 mg (0.2 times the recommended approved dose of 60 mg) of ALIQOPA in subjects with hepatic impairment, the geometric mean of total copanlisib C_max and AUC increased 1.38-fold and 1.71-fold, respectively, in subjects with moderate hepatic impairment (Child-Pugh B) as compared to normal hepatic function. The geometric mean unbound AUC of copanlisib was increased by 1.23-fold with no effect on C_max. The PK of copanlisib in patients with severe hepatic impairment (Child-Pugh C or total bilirubin = 3-10 x ULN and any AST) is unknown.

drug interaction studies

clinical studies

Effect of CYP3A and P-gp Inducers on Copanlisib

Rifampin, a strong CYP3A and a P-glycoprotein (P-gp) transporter inducer, administered at a dose of 600 mg once daily for 12 days with a single intravenous dose of 60 mg ALIQOPA in patients with cancer resulted in a 60% decrease in the mean AUC and a 12% decrease in C_max of copanlisib [see Drug Interactions ( 7.1 )].

Effect of CYP3A, P-gp and BCRP Inhibitors on Copanlisib

Itraconazole, a strong CYP3A inhibitor and a P-gp and Breast Cancer Resistance Protein (BCRP) transporter inhibitor, administered at a dose of 200 mg once daily for 10 days increased the mean AUC of a single intravenous dose of 60 mg ALIQOPA by 53% (or 1.53-fold) with no effect on C_max (1.03-fold) in patients with cancer [see Drug Interactions (7.1)].

in vitro studies

Effect of Transporters on Copanlisib:

Copanlisib is a substrate of P-gp and BCRP, but not a substrate for organic cation transporter (OCT) 1, OCT2, and OCT3, organic anion transporter (OAT) 1 and OAT3, organic anion-transporting polypeptide (OATP) 1B1 and OATP1B3, multidrug and toxin extrusion protein 1(MATE1) or MATE2-K.

Effect of Copanlisib on CYP and non-CYP Enzymes

Copanlisib is not an inhibitor of the metabolism of drugs that are substrates of the major CYP isoforms (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) or uridine diphosphate-glucuronosyltransferase isoforms (UGT) or dihydropyrimidine dehydrogenase (DPD) at therapeutic 60 mg dose plasma concentrations. Copanlisib is not an inducer of CYP1A2, CYP2B6 and CYP3A.

Effect of Copanlisib on Drug Transporter Substrates

Copanlisib is not an inhibitor of P-gp, BCRP, multi-drug resistance-associated protein (MRP2), bile salt export pump (BSEP), OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, and MATE1 at therapeutic 60 mg dose plasma concentrations.

Copanlisib is an inhibitor of MATE2-K (IC₅₀: 0.09 μM). Inhibition may occur after copanlisib infusion at approved recommended dosage. The clinical significance of this potential inhibition on plasma concentrations of concomitantly administered drugs that are MATE2-K substrates is unknown.

Carcinogenicity studies have not been conducted with copanlisib.

Copanlisib did not cause genetic damage in in vitro or in vivo assays.

Fertility studies with copanlisib were not conducted; however, adverse findings in male and female reproductive systems were observed in the repeat dose toxicity studies. Findings in the male rats and/or dogs included effects on the testes (germinal epithelial degeneration, decreased weight, and/or tubular atrophy), epididymides (spermatic debris, decreased weight, and/or oligospermia/aspermia), and prostate (reduced secretion and/or decreased weight). Findings in female rats included effects on ovaries (hemorrhage, hemorrhagic cysts, and decreased weight), uterus (atrophy, decreased weight), vagina (mononuclear infiltration), and a dose-related reduction in the numbers of female rats in estrus.

The efficacy of ALIQOPA was evaluated in a single-arm, multicenter, phase 2 clinical trial (NCT 01660451) CHRONOS-1 in a total of 142 subjects, which included 104 subjects with follicular B-cell non-Hodgkin lymphoma who had relapsed disease following at least two prior treatments. Patients must have received rituximab and an alkylating agent. Baseline patient characteristics are summarized in Table 5. The most common prior systemic therapies were chemotherapy in combination with anti-CD20 immunotherapy (89%), chemotherapy alone (41%), and anti-CD20 immunotherapy alone (37%). In CHRONOS-1, 34% of patients received two prior lines of therapy and 36% received three prior lines of therapy.

*Refractory: No response or progression of disease within six months of last treatment.

One hundred forty-two patients received 60 mg ALIQOPA; 130 patients received fixed dose 60 mg ALIQOPA and 12 patients received 0.8 mg/kg equivalent ALIQOPA administered as a 1-hour intravenous infusion on Days 1, 8, and 15 of a 28-day treatment cycle on an intermittent schedule (three weeks on and one week off). Treatment continued until disease progression or unacceptable toxicity. Tumor response was assessed according to the International Working Group response criteria for malignant lymphoma. Efficacy based on overall response rate (ORR) was assessed by an Independent Review Committee. Efficacy results from CHRONOS-1 are summarized in Table 6.

ORR = overall response rate; CI = confidence interval; CR = complete response;

PR = partial response; DOR = duration of response

*Kaplan-Meier estimate

The median time to response was 1.7 months (range 1.3 to 9.7 months).