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Pharmacokinetic-Pharmacodynamic Relationships of Apomorphine in Patients with Parkinson’s Disease

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  • Pharmacokinetic-Pharmacodynamic Relationships
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Abstract

In the treatment of patients with Parkinson’s disease, apomorphine has an established place as a back-up therapy if other antiparkinsonian drugs, such as levodopa and oral dopamine agonists, have not controlled the existing response fluctuations. Apomorphine is a synthetic derivative of morphine, with a totally distinct pharmacological profile. It is a very lipophilic compound which is easily (auto)oxidised. This (auto)oxidation is the main metabolic route besides glucuronidation and sulphation, which are both responsible for about 10% of the metabolic transformation.

Apomorphine quickly passes the nasal and intestinal mucosa as well as the blood-brain barrier (depending on the administration route). Many routes of administration have been explored, but subcutaneous, sublingual, nasal and rectal administration are used in clinical practice. The volume of distribution varies between 1 and 2 times bodyweight. The elimination half-life is very short (30 to 90 min) depending on the type of parenteral administration. Apomorphine is a high clearance drug (3 to 5 L/kg/h) and is mainly excreted and metabolised by the liver. Only 3 to 4% is excreted unchanged in the urine.

The clinical effect of apomorphine can be linked directly to its concentration in the cerebrospinal fluid. Consequently, a 2-compartment model can be used to predict the clinical effects of apomorphine. The pharmacokinetic-pharmacodynamic data reflect the clinical observations of steep dose-effect curves if apomorphine is used in patients with random ‘on-off’ fluctuations. These dose-effect curves are less steep in stable or ‘wearing-off’ (end-of-dose deterioration) patients.

Intravenous infusions of apomorphine in combination with timed motor assessments can be used clinically to characterise the therapeutic window of a particular patient if dyskinesia persists after single injections of apomorphine. If more population data become available, the population pharmacokinetics-pharmacodynamics of apomorphine could be helpful in predicting the clinical effects of apomorphine in the several subgroups of patients with Parkinson’s disease.

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References

  1. Parkinson J. An essay on the shaking palsy. London: Whittingham and Rowland, 1817.

    Google Scholar 

  2. Weil E. De L’apomorphine dans certain troubles nerveux. Lyon Med 1884; 48: 411–9.

    Google Scholar 

  3. Ernst AM. Relation between action of dopamine and apomorphine and the O-methylated derivatives upon the CNS. Psychopharmacologia 1965; 7: 391–9.

    Article  PubMed  CAS  Google Scholar 

  4. Wachtel H. Antiparkinsonian dopamine agonists: a review of the pharmacokinetics and neuropharmacology in animals and humans. J Neural Transm 1991; 3: 151–201.

    Article  CAS  Google Scholar 

  5. Cotzias GC, Papavasiliou PS, Tolosa ES, et al. Treatment of Parkinson’s disease with apomorphines. N Engl J Med 1976; 294: 567–72.

    Article  PubMed  CAS  Google Scholar 

  6. Agid Y, Bonnet AM, Pollak P, et al. Bromocriptine associated with a peripheral dopamine blocking agent in treatment of Parkinson’s disease. Lancet 1979; I: 570–2.

    Article  Google Scholar 

  7. Stibe CMH, Lees AJ, Kempster PA, et al. Subcutaneous apomorphine in parkinsonian on-off oscillations. Lancet 1988; I: 403–6.

    Article  Google Scholar 

  8. Lundgren P, Landersjo L. Stability and stabilization of apomorphine hydrochloride in aqueous solution. Acta Pharm Suec 1970; 7: 133–48.

    PubMed  CAS  Google Scholar 

  9. van Laar T, Jansen ENH, Essink AWG, et al. Intranasal apomorphine in parkinsonian on-off fluctuations. Arch Neurol 1992; 49: 482–4.

    Article  PubMed  Google Scholar 

  10. van Laar T, Jansen ENH, Neef C, et al. Pharmacokinetics and clinical efficacy of rectal apomorphine in patients with Parkinson’s disease: a study of five different suppositories. Mov Disord 1995; 10 (4): 433–9.

    Article  PubMed  Google Scholar 

  11. van Laar T, Neef C, Danhof M, et al. A new sublingual formulation of apomorphine in the treatment of patients with Parkinson’s disease. Mov Disord 1996; 11 (6): 633–8.

    Article  PubMed  Google Scholar 

  12. Gancher ST, Nutt JG, Woodward WR. Absorption of apomorphine by various routes in parkinsonism. Mov Disord 1991; 6: 212–6.

    Article  PubMed  CAS  Google Scholar 

  13. Priston MJ, Sewell GJ. Novel liquid Chromatographic assay for the low-level determination of apomorphine in plasma. J Chromatogr B 1996; 681: 161–7.

    Article  CAS  Google Scholar 

  14. Essink AWG, Lohuis CPGG, Klein Elhorst JT, et al. Selective and quantitative isolation and determination of apomorphine in human plasma. J Chromatogr B 1991; 570: 419–24.

    Article  CAS  Google Scholar 

  15. Van der Geest R, Kruger P, Gubbens-Stibbe JM, et al. Assay of R-apomorphine, S-apomorphine, apocodeine, isoapocodeine and their glucuronide and sulphate conjugates in plasma and urine of patients with Parkinson’s disease. J Chromatogr B 1997; 702: 131–41.

    Article  Google Scholar 

  16. Kaul PN, Brochman-Hanssen E, Way EL. Biological disposition of apomorphine. Urinary excretion and organ distribution of apomorphine. J Pharm Sci 1961; 50: 244–7.

    Article  PubMed  CAS  Google Scholar 

  17. Kaul PN, Conway MW. Induction and inhibition of in vivo glucuronidation of apomorphine in mice. J Pharm Sci 1971; 60: 93–5.

    Article  PubMed  CAS  Google Scholar 

  18. Missala K, Lal S, Sourkes TL. O-methylation of apomorphine and the metabolic prolongation of apomorphine-induced stereotyped behaviour. Eur J Pharmacol 1973; 22: 54–8.

    Article  PubMed  CAS  Google Scholar 

  19. Burkman AM. Some kinetic and thermodynamic characteristics of apomorphine degra dation. J Pharm Sci 1965; 54: 325–6.

    Article  PubMed  CAS  Google Scholar 

  20. Priston MJ, Sewell GJ. The analysis of apomorphine formulations for ambulatory infusions. Pharm Sci 1995; 1: 91–4.

    CAS  Google Scholar 

  21. Goldman ME, Kebabian JW. Aporphine enantiomers: interactions with D1 and D2 dopamine receptors. Mol Pharmacol 1984; 25: 18–23.

    PubMed  CAS  Google Scholar 

  22. Van der Geest R, Van Laar T, Kruger PP, et al. Pharmacokinetics, enantiomer interconversion and metabolism of R-apomorphine in patients with idiopathic Parkinson’s disease. Clin Neuropharmacol 1998; 21: 159–68.

    PubMed  Google Scholar 

  23. Danhof M, Mandema JW, Stijnen AM. Pharmacokinetic complexities of in vivo pharmacodynamic investigations. In: van Boxtel CJ, Holford NHG, Danhof M, editors. The in vivo study of drug action — concepts and applications of kineticdynamic modeling. Amsterdam: Elsevier Science Publishers, 1992: 31–60.

    Google Scholar 

  24. Przedborski S, Levivier M, Raftopoulos C, et al. Peripheral and central pharmacokinetics of apomorphine and its effect on dopamine metabolism in humans. Mov Disord 1995; 10: 28–36.

    Article  PubMed  CAS  Google Scholar 

  25. Gancher ST, Woodward WR, Gliessman P, et al. The short-duration response to apomorphine: implications for the mechanism of dopaminergic effects in parkinsonism. Ann Neurol 1990; 17: 45–52.

    Google Scholar 

  26. Hofstee DJ, Neef C, van Laar T, et al. Pharmacokinetics of apomorphine in Parkinson’s disease: plasma and cerebrospinal fluid levels in relation to motor responses. Clin Neuropharmacol 1994; 17: 45–52.

    Article  PubMed  CAS  Google Scholar 

  27. Dewey RB, Maraganore DM, Ahlskog JE, et al. A double-blind placebo-controlled study of intranasal apomorphine spray as a rescue agent for off-states in Parkinson’s disease. Mov Disord 1998; 13: 782–7.

    Article  PubMed  Google Scholar 

  28. Lees AJ, Montastruc JL, Turjanski N, et al. Sublingual apomorphine in Parkinson’s disease [comments]. J Neurol Neurosurg Psychiatry 1989; 51: 1440.

    Article  Google Scholar 

  29. Gancher ST, Woodward WR, Boucher B, et al. Peripheral pharmacokinetics of apomorphine in humans. Ann Neurol 1989; 26: 232–8.

    Article  PubMed  CAS  Google Scholar 

  30. Gancher GT, Nutt JG, Woodward WR. Time course of tolerance to apomorphine in parkinsonism. Clin Pharmacol Ther 1992; 52: 504–10.

    Article  PubMed  CAS  Google Scholar 

  31. Nicolle E, Pollak P, Serre-Debeauvais F, et al. Pharmacokinetics of apomorphine in parkinsonian patients. Fundam Clin Pharmacol 1993; 7: 245–52.

    Article  PubMed  CAS  Google Scholar 

  32. Van Laar T, Van der Geest R, Danhof M, et al. Stepwise intravenous infusion of apomorphine to determine the therapeutic window in patients with Parkinson’s disease. Clin Neuropharmacol 1998; 21: 152–8.

    PubMed  Google Scholar 

  33. Verhagen Metman L, Locatelli ER, Bravi D, et al. Apomorphine responses in Parkinson’s disease and the pathogenesis of motor complications. Neurology 1997; 48: 369–72.

    Article  PubMed  CAS  Google Scholar 

  34. Pollak P, Champay AS, Hommel M, et al. Subcutaneous apomorphine in Parkinson’s disease [letter]. J Neurol Neurosurg Psychiatry 1989; 52: 544.

    Article  PubMed  CAS  Google Scholar 

  35. Corboy DL, Wagner ML, Sage JI. Apomorphine for motor fluctuations and freezing in Parkinson’s disease. Ann Pharmacother 1995; 29: 282–8.

    PubMed  CAS  Google Scholar 

  36. Hughes AJ, Bishop S, Kleedorfer B, et al. Subcutaneous apomorphine in Parkinson’s disease; response to chronic administration for up to five years. Mov Disord 1993; 6: 165–70.

    Article  Google Scholar 

  37. Kraegen EW, Chrischolm DJ. Pharmacokinetics of insulin: implications for continuous subcutaneous insulin infusion therapy. Clin Pharmacokinet 1985; 10: 303–14.

    Article  PubMed  CAS  Google Scholar 

  38. Sam E, Sarre S, Michotte Y, et al. Distribution of apomorphine enantiomers in plasma, brain tissue and striatal extracellular fluid. Eur J Pharmacol 1997; 329: 9–15.

    Article  PubMed  CAS  Google Scholar 

  39. Neef C, Jelliffe RW, Van Laar T, et al. Population pharmacokinetics of apomorphine in patients with Parkinson’s disease. Drug Invest 1994; 7: 183–90.

    CAS  Google Scholar 

  40. Frankel JP, Lees AJ, Kempster PA, et al. Subcutaneous apomorphine in the treatment of Parkinson’s disease. J Neurol Neurosurg Psychiatry 1990; 53: 96–101.

    Article  PubMed  CAS  Google Scholar 

  41. Durif F, Jeanneau E, Serre-Debeauvais D, et al. Relation between plasma concentration and clinical efficacy after sublingual single dose apomorphine in Parkinson’s disease. Eur J Clin Pharmacol 1991; 41: 493–4.

    Article  PubMed  CAS  Google Scholar 

  42. Hughes AJ, Bishop S, Lees AJ, et al. Rectal apomorphine in Parkinson’s disease. Lancet 1991; 337: 118.

    Article  PubMed  CAS  Google Scholar 

  43. Van der Geest R, Danhof M, Bodde HE. Iontophoretic delivery of apomorphine; in vitro optimisation and validation. Pharm Res 1997; 14: 1797–802.

    Google Scholar 

  44. Van der Geest R, Van Laar T, Gubbens-Stibbe JM, et al. Iontophoretic delivery of R-apomorphine: an in vivo study in patients with Parkinson’s disease. Pharm Res 1997; 14: 1803–9.

    Google Scholar 

  45. Hughes AJ, Lees AJ, Stern GM. The motor response to sequential apomorphine in parkinsonian fluctuations. J Neurol Neurosurg Psychiatry 1991; 54: 358–60.

    Article  PubMed  CAS  Google Scholar 

  46. Grandas F, Gancher S, Lera G, et al. Time interval between repeated injections conditions: the duration of motor improvement to apomorphine in Parkinson’s disease. Neurology 1992; 42: 1287–90.

    Article  PubMed  CAS  Google Scholar 

  47. Gancher ST, Woodward WR, Nutt JG. Apomorphine tolerance in Parkinson’s disease: lack of a dose effect. Clin Neuropharmacol 1996; 19: 59–64.

    Article  PubMed  CAS  Google Scholar 

  48. Baas H, Harder S, Burklin F, et al. Pharmacodynamics of levodopa co-administered with apomorphine in Parkinsonian patients with end-of-dose motor fluctuations. Clin Neuropharmacol 1998; 21: 86–92.

    PubMed  CAS  Google Scholar 

  49. Gjedde A, Wong DF. Modeling neuroreceptor binding of radioligands in vivo. In: Frost JJ, Wagner HN, editors. Quantitative imaging: neuroreceptors, neurotransmitters and enzymes. New York: Raven Press, 1990: 51–80.

    Google Scholar 

  50. Kapoor R, Turjanski M, Frankel, et al. Intranasal apomorphine: a new treatment in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1990; 53: 1015.

    Article  PubMed  CAS  Google Scholar 

  51. Nutt JG, Holford NHG. The response to levodopa in Parkinson’s disease: imposing pharamcological law and order. Ann Neurol 1996; 39: 561–73.

    Article  PubMed  CAS  Google Scholar 

  52. Harder S, Baas H, Röger S, et al. PK-PD relationship of apomorphine in patients with Parkinson’s Disease [abstract PIII-77]. Clin Pharmacol Ther 1995; 59 (2): 207.

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Pharmacy, Medisch Spectrum Twente, P.O. Box 50000, 7500, KA Enschede, The Netherlands

    Cees Neef

  2. Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands

    Teus van Laar

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  1. Cees Neef
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  2. Teus van Laar
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Correspondence to Cees Neef.

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Neef, C., van Laar, T. Pharmacokinetic-Pharmacodynamic Relationships of Apomorphine in Patients with Parkinson’s Disease. Clin Pharmacokinet 37, 257–271 (1999). https://doi.org/10.2165/00003088-199937030-00004

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