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Importance of Within Subject Variation in Levodopa Pharmacokinetics: A 4Year Cohort Study in Parkinson’s Disease

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Abstract

The purpose of the study was to describe the population pharmacokinetics of levodopa in patients with Parkinson’s disease studied in 5 trials (10 occasions) over 4 years. Twenty previously untreated Parkinsonian patients were investigated. Each trial consisted of a 2-hr IV infusion of levodopa (1 mg/kg/h) with concomitant oral carbidopa given on two occasions separated by 72hr with no levodopa in between. This trial design was repeated at 6, 12, 24 and 48 months. A two-compartment pharmacokinetic model with central volume (V 1), peripheral volume (V 2), clearance (CL) and inter-compartmental clearance (CL ic ) was used to fit plasma levodopa concentrations. The model accounted for levodopa dosing prior to each trial and endogenous levodopa synthesis. Population parameter estimates (geometric mean) and population parameter variability (PPV; SD of normal distribution) were V 1 11.4 l/70 kg (0.44), CL 30.9 l/h/70 kg (0.25), V 2 27.3 l/70 kg (0.27), and CL ic 34.6 l/h/70 kg (0.48). PPV was partitioned into between subject variability (BSV) which was 0.12 V 1, 0.13 CL, 0.15 V 2, 0.28 CL ic , within trial variability (WTV) which was 0.16 V 1, 0.13 CL, 0.08 V 2, 0.18 CL ic and between trial variability (BTV) which was 0.40 V 1, 0.17 CL, 0.21 V 2, 0.34 CL ic. Neither structural nor random levodopa pharmacokinetic parameters were associated with the time course of development of fluctuation in motor response. Variability in levodopa pharmacokinetic parameters (particularly V 1) may result in variability in plasma levodopa concentrations that could contribute to fluctuations in motor response.

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References

  • O. Rascol DJ. Brooks AD. Korczyn P.P. Deyn ParticleDe C.E Clarke A.E. Lang (2000) ArticleTitleA five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group New Engl. J. Med. 342 1484–1491 Occurrence Handle1:CAS:528:DC%2BD3cXjvVeitrc%3D

    CAS  Google Scholar 

  • CD. McColl KA. Reardon M. Shiff P.A. Kempster (2002) ArticleTitleMotor response to levodopa and the evolution of motor fluctuations in the first decade of treatment of Parkinson’s disease Movement Disorders. 17 1227–1234 Occurrence Handle10.1002/mds.10244 Occurrence Handle12465061

    Article  PubMed  Google Scholar 

  • JG. Nutt JH. Carter ES. Lea G.J. Sexton (2002) ArticleTitleEvolution of the response to levodopa during the first 4 years of therapy Ann Neurol. 51 686–693 Occurrence Handle1:CAS:528:DC%2BD3sXhsFygsbw%3D

    CAS  Google Scholar 

  • J.G. Nutt (1987) ArticleTitleOn-Off phenomenon. Relation to levodopa pharmacokinetics and pharmacodynamics Ann. Neurol. 22 535–540 Occurrence Handle10.1002/ana.410220415 Occurrence Handle3324948 Occurrence Handle1:STN:280:DyaL1c7jt1Gqug%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • JA. Obeso VF. Grandas MR. Luquin M. Rodriguez G. Lera J.M Martinez-Lage (1989) ArticleTitleOvercoming pharmacokinetic problems in the treatment of Parkinson’s disease Mov. Disord. 4 S70–S85 Occurrence Handle10.1002/mds.870040510 Occurrence Handle2657410

    Article  PubMed  Google Scholar 

  • J.L. Juncos (1992) ArticleTitleLevodopa, Pharmacology, Pharmacokinetics, and Pharmacodynamics Neurol. Clin. 10 487–509 Occurrence Handle1584186 Occurrence Handle1:STN:280:By2B287ltlY%3D

    PubMed  CAS  Google Scholar 

  • I. Shoulson GA. Glaubiger T.N. Chase (1975) ArticleTitleOn-off response. Clinical and biochemical correlations during oral and intravenous levodopa administration in parkinsonian patients Neurology 25 1144–1148 Occurrence Handle812004 Occurrence Handle1:STN:280:CSmD2sngs1U%3D

    PubMed  CAS  Google Scholar 

  • RJ. Hardie AJ. Lees G.M. Stern (1984) ArticleTitleOn-off fluctuations in Parkinson’s disease. A clinical and neuropharmacological study Brain 107 487–506 Occurrence Handle6722513

    PubMed  Google Scholar 

  • N. Quinn JD. Parkes C.D. Marsden (1984) ArticleTitleControl of on/off phenomenon by continuous intravenous infusion of levodopa Neurology 34 1131–1136 Occurrence Handle6540399 Occurrence Handle1:STN:280:BiuB2s7hvFI%3D

    PubMed  CAS  Google Scholar 

  • J.G. Nutt J.H. Fellman (1984) ArticleTitlePharmacokinetics of levodopa Clin Neuropharmacol. 7 35–49 Occurrence Handle6367973 Occurrence Handle1:CAS:528:DyaL2cXhs1Oms7k%3D

    PubMed  CAS  Google Scholar 

  • RJ. Hardie SL. Malcolm AJ. Lees GM. Stern J.G. Allen (1986) ArticleTitleThe pharmacokinetics of intravenous and oral levodopa in patients with Parkinson’s disease who exhibit on-off fluctuations Br. J. Clin. Pharmacol. 22 429–436 Occurrence Handle3533125 Occurrence Handle1:STN:280:DyaL2s%2Fis1Cntg%3D%3D

    PubMed  CAS  Google Scholar 

  • M. Contin R. Riva P. Martinelli P. Cortelli F. Albani A. Baruzzi (1994) ArticleTitleLongitudinal monitoring of the levodopa concentration-effect relationship in Parkinson’s disease Neurology 44 1287–1292 Occurrence Handle8035932 Occurrence Handle1:STN:280:ByuA3cbotFc%3D

    PubMed  CAS  Google Scholar 

  • G. Fabbrini J. Juncos MM. Mouradian C. Serrati T.N. Chase (1987) ArticleTitleLevodopa pharmacokinetic mechanisms and motor fluctuations in Parkinson’s disease Ann. Neurol. 21 370–376 Occurrence Handle10.1002/ana.410210409 Occurrence Handle3579222 Occurrence Handle1:STN:280:BiiB3M7nvFc%3D

    Article  PubMed  CAS  Google Scholar 

  • JG. Nutt WR. Woodward JH. Carter S.T. Gancher (1992) ArticleTitleEffect of long-term therapy on the pharmacodynamics of levodopa. Relation to on-off phenomenon Arch. Neurol. 49 1123–1130 Occurrence Handle1444877 Occurrence Handle1:STN:280:ByyD2svltFc%3D

    PubMed  CAS  Google Scholar 

  • M. Contin R. Riva P. Martinelli A. Baruzzi (1993) ArticleTitlePharmacodynamic modeling of oral levodopa: Clinical application in Parkinson’s disease Neurology 43 367–371 Occurrence Handle8437704 Occurrence Handle1:STN:280:ByyC2szjtFY%3D

    PubMed  CAS  Google Scholar 

  • N.H.G. Holford (2001) ArticleTitleTarget concentration intervention: beyond Y2K Br. J. Clin. Pharmacol. 52 55S–59S Occurrence Handle10.1046/j.1365-2125.2001.00971.x Occurrence Handle11564053

    Article  PubMed  Google Scholar 

  • M.O. Karlsson L.B. Sheiner (1993) ArticleTitleThe importance of modeling interoccasion variability in population pharmacokinetic analyses J Pharmacokinet. Biopharmaceutics 21 735–750 Occurrence Handle1:STN:280:ByuC1cnpt10%3D

    CAS  Google Scholar 

  • AJ. Hughes Y. Ben-Shlomo SE. Daniel A.J. Lees (1992) ArticleTitleWhat features improve the accuracy of clinical diagnosis in Parkinson’s disease: a clinicopathologic study Neurology 42 1142–1146 Occurrence Handle1603339 Occurrence Handle1:STN:280:By2B1MzltlY%3D

    PubMed  CAS  Google Scholar 

  • DJ. Gelb E. Oliver S. Gilman (1999) ArticleTitleDiagnostic criteria for Parkinson disease Arch. Neurol. 56 33–39 Occurrence Handle10.1001/archneur.56.1.33 Occurrence Handle9923759 Occurrence Handle1:STN:280:DyaK1M7itVKgtg%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • JG. Nutt JH. Carter W.R. Woodward (1994) ArticleTitleEffect of brief levodopa holidays on the short-duration response to levodopa. Evidence for tolerance to the antiparkinsonian effects Neurology 44 1617–1622 Occurrence Handle7936285 Occurrence Handle1:STN:280:ByqD383isV0%3D

    PubMed  CAS  Google Scholar 

  • JG. Nutt JH. Carter L. Van Houten W.R. Woodward (1997) ArticleTitleShort- and long-duration responses to levodopa during the first year of levodopa therapy Ann. Neurol. 42 349–355 Occurrence Handle10.1002/ana.410420311 Occurrence Handle9307256 Occurrence Handle1:CAS:528:DyaK2sXmt1yjtbw%3D

    Article  PubMed  CAS  Google Scholar 

  • JG. Nutt WR. Woodward JP. Hammerstad JH. Carter J.L Anderson (1984) ArticleTitleThe “on-off” phenomenon in Parkinson’s disease. Relation to levodopa absorption and transport New Engl. J. Med. 310 483–488 Occurrence Handle6694694 Occurrence Handle1:STN:280:DyaL2c7hsleqtw%3D%3D

    PubMed  CAS  Google Scholar 

  • N.H.G. Holford (2003) Input-output models HC. Kimko SB. Duffull (Eds) Simulation for Designing Clinical Trials. A Pharmacokinetic–Pharmacodynamic Modeling Perspective Marcel Dekker Inc. New York 17–29

    Google Scholar 

  • N.H.G. Holford (1996) ArticleTitleA size standard for pharmacokinetics Clin Pharmacokinet. 30 329–332 Occurrence Handle8743333 Occurrence Handle1:STN:280:BymA3s%2Fms10%3D Occurrence Handle10.2165/00003088-199630050-00001

    Article  PubMed  CAS  Google Scholar 

  • Beal SL., Boeckmann AJ., and L. B. Sheiner. NONMEM Project Group NONMEM Users Guides Version V. University of California at San Francisco, San Francisco, 1999

  • U. Wählby EN. Jonsson M.O. Karlsson (2001) ArticleTitleAssessment of the actual significance levels for covariate effects in NONMEM J. Pharmacokinet. Pharmacodyn. 28 23–252

    Google Scholar 

  • J.V.S. Gobburu J. Lawrence (2002) ArticleTitleApplication of resampling techniques to estimate exact significance levels for covariate selection during nonlinear mixed effects model building: Some inferences Pharm. Res. 19 92–98 Occurrence Handle10.1023/A:1013615701857 Occurrence Handle11841044 Occurrence Handle1:CAS:528:DC%2BD38XhtVSmtr4%3D

    Article  PubMed  CAS  Google Scholar 

  • K. Jorga L. Banken B. Fotteler P. Snell J.L. Steimer (2000) ArticleTitlePopulation pharmacokinetics of levodopa in patients with Parkinson’s disease treated with tolcapone Clin. Pharmacol. & Therapeut. 67 610–620 Occurrence Handle1:CAS:528:DC%2BD3cXltFSitLc%3D

    CAS  Google Scholar 

  • EJ. Triggs BG. Charles M. Contin P. Martinelli P. Cortelli R Riva F. Albani A. Baruzzi (1996) ArticleTitlePopulation pharmacokinetics and pharmacodynamics of oral levodopa in parkinsonian patients Eur. J. Clin. Pharmacol. 51 59–67 Occurrence Handle10.1007/s002280050161 Occurrence Handle8880053 Occurrence Handle1:CAS:528:DyaK28Xms1Klt7o%3D

    Article  PubMed  CAS  Google Scholar 

  • JG. Nutt WR. Woodward J.L. Anderson (1985) ArticleTitleThe effect of carbidopa on the pharmacokinetics of intravenously administered levodopa The mechanism of action in the treatment of parkinsonism Ann. Neurol. 18 537–543 Occurrence Handle10.1002/ana.410180505 Occurrence Handle4073849 Occurrence Handle1:STN:280:DyaL28%2FnsFygsw%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • ST. Gancher JG. Nutt W.R. Woodward (1987) ArticleTitlePeripheral pharmacokinetics of levodopa in untreated, stable and fluctuating parkinsonian patients Neurology 37 940–944 Occurrence Handle3587644 Occurrence Handle1:STN:280:DyaL2s3ivFGmsg%3D%3D

    PubMed  CAS  Google Scholar 

  • KC. Yeh TF. August DF. Bush KC. Lasseter DG. Musson S Schwartz ME. Smith D.C. Titus (1989) ArticleTitlePharmacokinetics and bioavailability of Sinemet CR: A summary of human studies Neurology 39 25–38 Occurrence Handle2685649 Occurrence Handle1:STN:280:By%2BD28jgs10%3D

    PubMed  CAS  Google Scholar 

  • S. Grange N.HG. Holford T.W. Guentert (2001) ArticleTitleA pharmacokinetic model to predict the PK interaction of L-Dopa and benserazide in rats Pharm. Res. 18 1174–1184 Occurrence Handle10.1023/A:1010935228654 Occurrence Handle11587490 Occurrence Handle1:CAS:528:DC%2BD3MXnt1ekt7Y%3D

    Article  PubMed  CAS  Google Scholar 

  • M.O. Karlsson L.B. Sheiner (1994) ArticleTitleEstimating Bioavailability when Clearance Varies with Time Clin. Pharmacol. & Therapeut. 55 623–637 Occurrence Handle1:STN:280:ByuB2szktF0%3D

    CAS  Google Scholar 

  • M.J. du Preez JH. Botha ML. McFadyen N.H.G. Holford (1999) ArticleTitleThe pharmacokinetics of theophylline in premature neonates during the first few days after birth Ther. Drug Monit. 21 598–603 Occurrence Handle10.1097/00007691-199912000-00003 Occurrence Handle10604818 Occurrence Handle1:CAS:528:DC%2BD3cXktFGg

    Article  PubMed  CAS  Google Scholar 

  • AD. Huitema RA. Mathot MM. Tibben JH. Schellens S. Rodenhuis J.H. Beijnen (2001) ArticleTitlePopulation pharmacokinetics of thioTEPA and its active metabolite TEPA in patients undergoing high-dose chemotherapy Br. J. Clin. Pharmacol. 51 61–70 Occurrence Handle10.1046/j.1365-2125.2001.01301.x Occurrence Handle11167666 Occurrence Handle1:CAS:528:DC%2BD3MXhtF2hu7Y%3D

    Article  PubMed  CAS  Google Scholar 

  • I. Kuruma G. Bartholini R. Tissot A. Pletscher (1971) ArticleTitleThe metabolism of L-3-O-Methyldopa, a precursor of dopa in man Clin Pharmcol. and Therapeut. 12 678–682 Occurrence Handle1:STN:280:CS6B1c3hs1U%3D

    CAS  Google Scholar 

  • NS. Sharpless MD. Muenter GM. Tyce C.A. Owen (1972) ArticleTitle3-Methoxy-4-hydroxyphenylalanine (3-O-Methyldopa) in plasma during L-dopa therapy of patients with Parkinson’s disease Clin Chim. Acta 37 359–369 Occurrence Handle1:CAS:528:DyaE38XktVSrsLs%3D

    CAS  Google Scholar 

  • MD. Muenter NS. Sharpless G.M. Tyce (1972) ArticleTitlePlasma 3-O-Methyldopa in L-dopa therapy of Parkinson’s disease Mayo Clin Proc. 47 389–395 Occurrence Handle5041685 Occurrence Handle1:STN:280:CS2B38blt1E%3D

    PubMed  CAS  Google Scholar 

  • J.G. Nutt N.H.G. Holford (1996) ArticleTitleThe response to levodopa in Parkinson’s disease: Imposing pharmacological law and order Ann. Neurol. 39 561–573 Occurrence Handle10.1002/ana.410390504 Occurrence Handle8619540 Occurrence Handle1:CAS:528:DyaK28XjsFags7w%3D

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand

    Phylinda L. S. Chan & Nicholas H. G. Holford

  2. Department of Neurology, Physiology and Pharmacology, Portland VA Medical Center and Oregon Health Sciences University, Portland, USA

    John G. Nutt

  3. Pfizer Inc., 2800 Plymouth Road, Ann Arbor, Michigan, MI, 48105, USA

    Phylinda L. S. Chan

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  1. Phylinda L. S. Chan
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  2. John G. Nutt
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  3. Nicholas H. G. Holford
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Correspondence to Phylinda L. S. Chan.

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Chan, P.L.S., Nutt, J.G. & Holford, N.H.G. Importance of Within Subject Variation in Levodopa Pharmacokinetics: A 4Year Cohort Study in Parkinson’s Disease. J Pharmacokinet Pharmacodyn 32, 307–331 (2005). https://doi.org/10.1007/s10928-005-0039-x

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