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<title>12 CLINICAL PHARMACOLOGY</title>
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<code code="43679-0" codeSystem="2.16.840.1.113883.6.1" displayName="MECHANISM OF ACTION SECTION"/>
<title>12.1 Mechanism of Action</title>
<text>
<paragraph>Danicopan binds reversibly to complement Factor D and selectively inhibits the alternative complement pathway. Danicopan prevents the cleavage of complement Factor B into the Ba and Bb fragments which are required for the formation of the alternative pathway (AP) complement component C3 convertase (C3bBb), the generation of downstream effectors including C3 fragment opsonization, and the amplification of the terminal pathway.</paragraph>
<paragraph>In PNH, intravascular hemolysis (IVH) is mediated by the terminal membrane attack complex (MAC), while extravascular hemolysis (EVH) is facilitated by C3 fragment opsonization. Danicopan acts proximally in the alternative pathway of the complement cascade to control preferentially C3 fragment-mediated EVH, while co-administered ravulizumab or eculizumab is anticipated to maintain control over MAC-mediated IVH.</paragraph>
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<code code="43681-6" codeSystem="2.16.840.1.113883.6.1" displayName="PHARMACODYNAMICS SECTION"/>
<title>12.2 Pharmacodynamics</title>
<text>
<paragraph>Danicopan inhibits the AP of the complement system, as demonstrated by the decrease in ex vivo serum AP activity and in vivo plasma Bb concentration. Danicopan also reduces complement C3 fragment deposition on circulating red blood cells (RBCs) in PNH patients.</paragraph>
<paragraph>In patients with PNH undergoing treatment with ravulizumab or eculizumab, co-administration of VOYDEYA from 150 mg three times a day to 200 mg three times a day inhibited AP activity by >90%. Additionally, plasma Bb levels decreased by about 50% and the fraction of circulating PNH RBCs with measured C3 fragment deposition decreased by over 50%.</paragraph>
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<paragraph>
<content styleCode="underline">Cardiac Electrophysiology</content>
</paragraph>
<paragraph>At a single-dose of 1200 mg that results in approximately 2 times the peak concentration achieved following 200 mg three times a day, VOYDEYA does not prolong the QTc interval to any clinically relevant extent.</paragraph>
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<title>12.3 Pharmacokinetics</title>
<text>
<paragraph>At the recommended dosages of 150 or 200 mg three times a day, the median systemic exposure of danicopan at steady state has a maximum plasma concentration (C<sub>max,ss</sub>) of 535 or 665 ng/mL, respectively, and has an area under the plasma drug concentration time curve (AUC<sub>24,ss</sub>) of 8180 or 10200 ng × h/mL, respectively.</paragraph>
<paragraph>Danicopan exposures at steady state generally increase in a dose-proportional manner from 150 mg three times a day to 200 mg three times a day. Danicopan systemic exposure reaches steady state in approximately 2 days. An approximately 2-fold accumulation of danicopan exposure is expected at steady state following thrice daily dosing compared to a single dose.</paragraph>
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<paragraph>
<content styleCode="underline">Absorption</content>
</paragraph>
<paragraph>The median time to maximum drug concentration (T<sub>max</sub>) is 3.7 hours following oral administration of 150 mg danicopan in patients with PNH.</paragraph>
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<paragraph>
<content styleCode="italics">Effect of Food</content>
</paragraph>
<paragraph>When the danicopan tablet was administered with a high-fat meal, danicopan AUC and C<sub>max</sub> were approximately 25%, and 93% higher, respectively, compared to the fasted state. Median time to maximum drug concentration (T<sub>max</sub>) was comparable when danicopan was administered in the fed or fasted state at approximately 3.0 and 2.5 hours, respectively.</paragraph>
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<paragraph>
<content styleCode="underline">Distribution</content>
</paragraph>
<paragraph>Plasma protein binding of danicopan is 91.5% to 94.3%. Danicopan is mainly distributed in plasma with a whole blood to plasma distribution ratio of 0.545. The apparent volume of distribution for a 75 kg person was 395 L.</paragraph>
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<paragraph>
<content styleCode="underline">Elimination</content>
</paragraph>
<paragraph>The mean half-life (t<sub>½</sub>) is 7.9 hours. The mean apparent clearance of danicopan is 63 L/h.</paragraph>
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<paragraph>
<content styleCode="italics">Metabolism</content>
</paragraph>
<paragraph>Danicopan is extensively metabolized (96%) via oxidation, reduction, and hydrolysis pathways, with amide hydrolysis being the major pathway of elimination. Metabolism by CYP-mediated pathways is minimal.</paragraph>
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<paragraph>
<content styleCode="italics">Excretion</content>
</paragraph>
<paragraph>After a single oral administration of 150 mg [<sup>14</sup>C]-danicopan in humans, 69% of total radioactivity (danicopan plus metabolites) was excreted in feces and 25% was excreted in urine. Unchanged danicopan accounted for 3.57% and 0.48% of the dose excreted in feces and urine, respectively.</paragraph>
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<paragraph>
<content styleCode="underline">Specific Populations</content>
</paragraph>
<paragraph>No clinically significant differences in the pharmacokinetics of danicopan were observed based on sex, age (16.9 to 82 years), or race (Caucasians and Asians) based on population pharmacokinetic (PK) assessment.</paragraph>
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<paragraph>
<content styleCode="italics">Renal Impairment</content>
</paragraph>
<paragraph>Following oral administration of danicopan 200 mg in subjects with severe renal impairment (eGFR < 30 mL/min/1.73 m<sup>2</sup>), the extent of danicopan exposure (AUC<sub>0-inf</sub>) increased by 52% as compared to subjects with normal renal function. There was no clinically meaningful change in C<sub>max</sub> and T<sub>max</sub>.</paragraph>
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<paragraph>
<content styleCode="italics">Hepatic Impairment</content>
</paragraph>
<paragraph>Danicopan C<sub>max</sub> decreased by 27% and AUC<sub>0-inf</sub> decreased by 8% in subjects with moderate hepatic impairment (Child-Pugh B). Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C).</paragraph>
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<paragraph>
<content styleCode="underline">Drug Interaction Studies</content>
</paragraph>
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<paragraph>
<content styleCode="italics">Clinical Studies</content>
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<section>
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<paragraph>
<content styleCode="italics">Effect of Danicopan on the Pharmacokinetics of Other Drugs:</content>
</paragraph>
<paragraph>Dedicated clinical drug interaction studies showed no clinically significant drug interactions with danicopan as an inhibitor or inducer of CYP2B6 (bupropion), CYP2C9 (warfarin), CYP2C19 (omeprazole), CYP3A4 (midazolam), and UGT1A1 and UGT2B7 (mycophenolic acid).</paragraph>
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<paragraph>
<content styleCode="italics underline">BCRP Substrates</content>
</paragraph>
<paragraph>Co-administration of a single oral dose of rosuvastatin 20 mg with danicopan dosed to steady state (200 mg three times a day for 4 days) resulted in increased rosuvastatin C<sub>max</sub> and AUC<sub>0-inf</sub> by 3.3-fold and 2.2-fold, respectively.</paragraph>
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<text>
<paragraph>
<content styleCode="italics underline">P-gp Substrates</content>
</paragraph>
<paragraph>Co-administration of a single oral dose of fexofenadine 180 mg with danicopan dosed to steady state (150 mg three times a day for 4 days) resulted in increased fexofenadine C<sub>max</sub> and AUC<sub>0-inf</sub> by 1.4-fold and 1.6-fold, respectively.</paragraph>
<paragraph>Co-administration of a single oral dose of tacrolimus 2 mg with danicopan dosed to steady state (200 mg three times a day for 5 days) resulted in increased tacrolimus C<sub>max</sub> and AUC<sub>0-inf</sub> by 1.1-fold and 1.5-fold, respectively.</paragraph>
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<paragraph>
<content styleCode="italics">Effect of Other Drugs on the Pharmacokinetics of Danicopan:</content>
</paragraph>
<paragraph>No clinically significant drug interactions were observed for danicopan as a victim when co-administered with antacid drugs (calcium carbonate, aluminum/magnesium hydroxide/simethicone) or a proton pump inhibitor (omeprazole).</paragraph>
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<paragraph>
<content styleCode="italics">In Vitro Studies</content>
</paragraph>
<paragraph>Non-CYP based metabolism is the predominant clearance pathway for danicopan. The minimal contribution of CYP metabolism in human hepatocytes is suggestive of a very low likelihood of danicopan as a victim of CYP-based drug-drug interactions.</paragraph>
<paragraph>Danicopan is a substrate of P-gp, but not a substrate of BCRP, Organic Anion Transporting Polypeptide 1B1 (OATP1B1), or OATP1B3. Danicopan is not an inducer of CYP1A2, CYP2B6 or CYP2C9.</paragraph>
<paragraph>Danicopan is an inhibitor of BCRP and P-gp, but not an inhibitor of transporters OATP1B1, OATP1B3, Organic Anion Transporter (OAT)1, OAT3, Organic Cation Transporter 2 (OCT2), or Multidrug And Toxin Extrusion 1 and 2K (MATE1 and MATE2-K).</paragraph>
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