Modulation of Drug Transporters to Enhance Oral Bioavailability

1
Modulation of Drug Transporters to Enhance Oral
Bioavailability

• Roxanne C. Jewell, Ph.D.
• 8 March 2005

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Elacridar (GF120918)

• Potent inhibitor of P-gp (IC50 20 nM)
• Identified as inhibitor of BCRP (ABCG2) in 1998 -
  near complete inhibition at 100 nM
• Not inhibitor of MRP1 and MRP2
• CYP3A4 and CYP2C19 substrate
• Not inhibitor of CYP1A2, CYP2C9, CYP2C19, CYP2D6,
  CYP3A4

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Elacridar - Clinical Pharmacokinetics

• Linear pharmacokinetics in healthy volunteers up
  to 100 mg
• Increase in exposure with increasing dose at
  higher doses - less than dose-proportional
• Food effect - high fat gt low fat gt fasted
• Drug interaction with ketoconazole - 6-7-fold
  increase in elacridar AUC, 3-fold increase in Cmax

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Rhodamine 123 Accumulation in CD56 Cells After
Elacridar Administration
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Topotecan

• Topoisomerase I inhibitor approved for ovarian
  and small cell lung cancer
• Active form - lactone undergoes pH-dependent
  ring opening to inactive carboxylate form
• Total topotecan lactone carboxylate
• Approved dosing 1.5 mg/m2/d X 5 d q21d iv
• Under study 2.3 mg/m2/d X 5d q21d po
• Oral bioavailability of topotecan 40
• P-gp and BCRP substrate

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Clinical Proof of Principle(Kruijtzer et al., J.
Clin. Oncol. 2002 202943-2950)

• Study design
• Cohort A (n8) - 1.0 mg/m2 oral topotecan /-
  1000 mg elacridar 60 min prior to topotecan,
  randomized on D1 and D8, iv topotecan on D15-19
• Cohort B (n8) - 1.0 mg/m2 iv topotecan /- 1000
  mg elacridar 60 min prior to topotecan,
  randomized on D1 and D8, iv topotecan on D15-19

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Dose Rationale

• Proof of principle - elacridar dose highest
  single dose level previously tested - 1000 mg
• Topotecan dose - 2/3 of labeled iv dose level to
  allow for increased exposure due to potential
  effects on clearance
• Topotecan given by oral administration of iv
  solution

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Change in Topotecan AUC with Elacridar
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Total Topotecan Results
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Bioavailability Summary

• Total topotecan F(1) 40.0 without elacridar
  and 97.1 with elacridar (assumes constant CL)
• Total topotecan F(2) 81.7 with elacridar
  (accounts for change in topotecan CL)
• Interpatient variability of F decreased from 17
  without elacridar to 11 with elacridar

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Intravenous Topotecan

• No significant difference in topotecan
  lactone/total topotecan AUC ratio with elacridar.
• Urinary excretion of total topotecan was not
  significantly different with and without
  elacridar.
• No significant difference in N-desmethyl
  topotecan Cmax and AUC with elacridar.
• Urinary excretion of N-desmethyl topotecan low on
  both occasions.

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Oral Topotecan

• No significant difference in topotecan
  lactone/total topotecan AUC ratio with elacridar.
  
• Urinary excretion of total topotecan increased
  from 14.9 ? 3.7 of dose without elacridar to
  35.1 ? 12.8 with elacridar.
• N-desmethyl topotecan AUC and Cmax increased with
  elacridar.
• No significant difference in urinary excretion of
  N-desmethyl topotecan.

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Conclusions

• Co-administration of elacridar increased apparent
  oral bioavailability of topotecan from 40 to
  97.
• Elacridar resulted in 10 decrease in topotecan
  systemic clearance.
• Accounting for decreased clearance, oral
  bioavailability of total topotecan was 81.7 with
  elacridar.
• There were no obvious effects on topotecan
  metabolism or urinary elimination.

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Elacridar/Topotecan Dose-Finding

• Two parts- determine minimum elacridar dose
  and appropriate timing (simultaneous or 60 min
  prior) for maximum topotecan exposure at fixed
  topotecan dose (2.0 mg) given as capsule-
  determine MTD of topotecan capsules at selected
  elacridar dose on daily X 5 every 21 days schedule

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Conclusions

• Elacridar at 100 mg given simultaneously with
  topotecan capsule is sufficient for maximal
  exposure.
• MTD of oral topotecan in combination with 100 mg
  elacridar daily X 5 every 21 days is 2.0 mg -
  appears to be well-tolerated in heavily and
  mildly pretreated patients.
• The toxicity profile of oral topotecan and
  elacridar seems to be consistent with the
  toxicity profile of IV topotecan on the same
  schedule.

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Paclitaxel

• Cremophor EL - hypersensitivity and nonlinear
  pharmacokinetics after iv administration
• Very low oral bioavailability (lt10)
• P-gp substrate
• CYP2C8 and CYP3A4 substrate
• P-gp limits oral uptake of paclitaxel and
  mediates direct excretion into intestinal lumen

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Preclinical Paclitaxel Bioavailability(Bardelmeij
er et al., Clin. Cancer Res. 2000 64416-4421)
? wild-type vehicle ? mdr1a/1b knockout
vehicle ? wild-type elacridar ? mdr1a/1b
knockout elacridar
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Clinical Proof of Principle(Malingré et al., Br.
J. Cancer 2001 8442-47)

• Study design Randomized crossover study of oral
  paclitaxel at 120 mg/m2 60 min after 1000 mg oral
  elacridar or iv paclitaxel at 175 mg/m2 infused
  over 3 h (n6)
• Proof of principle - elacridar dose highest
  single dose level previously tested - 1000 mg
• Paclitaxel dose - 2/3 of labeled iv dose level
  to allow for increased exposure due to potential
  effects on clearance
• Paclitaxel given by oral administration of iv
  formulation

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Clinical Paclitaxel Bioavailability

• Oral IV
• AUC (µM.h) 3.27 ? 1.67 15.92 ? 2.46
• Tgt0.1 µM (h) 7.5 ? 4.7 16.6 ? 4.2
• F () 30 ? 15
• F 30 assuming linearity - underestimates true
  value cross-study estimate using data from iv
  paclitaxel at 125 mg/m2 over 3 h 50

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Clinical Paclitaxel Bioavailability

• Paclitaxel AUC with cyclosporin A 2.55 ? 2.29
  µM.h (n3). Paclitaxel exposure with elacridar
  comparable to exposure with CsA, which showed a
  7-fold increase in F.
• Conclusion Elacridar is a good,
  non-immunosuppressive alternative to cyclosporin
  A in enhancing the oral bioavailability of
  paclitaxel.

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Summary

• Elacridar - potent inhibitor of P-gp and BCRP
  without CYP inhibition
• Enhanced exposure after oral administration of
  topotecan (P-gp and BCRP substrate) and
  paclitaxel (P-gp substrate)
• Elacridar at 100 mg simultaneously with topotecan
  sufficient for this effect
• Toxicity profile of oral topotecan/elacridar
  consistent with toxicity profile of iv topotecan
  on same dosing schedule

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Acknowledgments

• Netherlands Cancer Institute GlaxoSmithKlineJan
  Schellens Charlotte BaidooHeleen
  Bardelmeijer Ken BrouwerJos Beijnen
  Wendy Girling
• Hans Jonker Jenny HuangCMF
  Kruijtzer François Hyafil Isa
  Kuppens Steve MangumMirte Malingré
  Henk Mos Hilde Rosing Elaine
  PaulWW ten Bokkel Huinink Keith
  WardOlaf van Tellingen