Dose extrapolation from - PowerPoint Presentation

1. Dose extrapolation from in vitro to in vivoand across speciesPierre-Louis ToutainRoyal veterinary College London & project officer at the ENV of Toulouse Wuhan University October 2017

2. How to determine a dose?Experimentally: The dose-titration trialNon experimentally: by extrapolation

3. Dose determination: The parallel designComplicateCostlyEthical aspect (experimetal model) PlaceboDoseResponse123**NSSelected dose

4. Many major and minor species in veterinary medicine Impossible to determine experimentally a dose for all species

5. Range of body size within species require extrapolationAdult to adultYoung to adult

6. As it is impossible to determine an experimental dose for all species and breeds , how to extrapolate a dose from an other species or within a given species or from in vitro data?

7. The different possible extrapolations to determine a doseUsing In vivo data Between speciesFrom rat/man to dogs Within speciesFrom preruminant calf to adult cowFrom in vitro (or ex vivo) to in vivo

8. Dose extrapolation within a given species

9. Dose individualisation in petsSize matters !Dose /kg BW

10. Scaling dose per Kg body weight for the within species extrapolation is routinely used in veterinary medicine Is it always appropriate ?

11. Is dose normalisation per kg BW sufficient?Assessment of GFR in a large healthy canine population582 pure-breed dogs 49 breedsPlasma exogenous creatinine clearance testIV bolus : 40 mg/kgBS: 0, 5, 10 min, 1,2,4,6,8 hAssay: enzymatic method (Vitros 250)Lefebvre HP. Etude KINDO

12. 54.2 ± 6.1kgLefebvre HP. Etude KINDO BW influence not correctly taken into account (allometric rules)2.8 ± 0.4 kgBody Weight

13. Great DaneN=754.2±6.1 kg2.8±0.3 mL/min/kgBeagleN=1112.9±2.9 kg2.9±0.5 mL/min/kgLefebvre HP American College of Veterinary Internal Medicine. 28th Annual Forum, Anaheim, USA, June 9-12, 2010. Etude KINDO Suggests that breed has an impact in addition to BW !

14. Scaling using the body surface area (BSA) as an alternative to the scaling by body weight

15. 15Cancer Res 1958 28 853-856it was seen that the doses per unit of body weight of mechlorethamine, methotrexate, actinomycin D, and TSPAare greater in smaller animals than in larger ones, and higher in children than in adults. The doses per unit of surface area are nearly similar for all species and for all ages of humans.

16. Methotrexate dosage ECVPT-2009 16SpeciesBW (kgBSA (m2)Dose/day/mgDose/daymg/kgDose/dayMg/m2Mouse0.0180.00750.0221.53.6rat0.250.0450.1250.52.8Infant80.41.250.153.1Child200.82.50.123.1Adult701.8550.072.7

17. 17Comparison of toxicity data on anticancer agents for the Swiss mouse and man (on a mg per m2 basis)Mouse LD10 mg per m2Maximum tolerated dose (mg per m2)1000100101.00.1101000AntimetabolitesAlkylating agentsOthers From Freireich et al 1966

18. Introduction of BSA in veterinary medicine for oncology

19. BSA is not directly measured but estimated with allometric equations

20. ECVPT-2009 20

21. The case of doxorubicin30 mg/m2 Doxorubicin Dogs <10 kg received more than 1.5 mg/kgIncreased incidence of toxicityDogs >10 kg received less than 1.0 mg/kgArrington et al. AJVR 55(11) 1587-92

22. 22Body weight or body surface area?No scientific backgroundMany examples for which BSA is not appropriate in human medicineConclusion: There is no advantage using BSA over BW

23. Population PK has to replace the outdated BSA lawECVPT-2009 23

24. Dose extrapolation: from empiric (scaling) to mechanistic (physiological) approaches

25. What is exactly a Dose?

26. Dose titrationDoseResponseBlack boxPK/PDDosePKPDPlasmaconcentrationResponseA dose is a PK/PD variable

27. 27A fundamental relationshipA ose can be determined rationally using a PK/PD concept! For a linear kinetic , clearance is a scaling parameter between a dose and plasma concentration

28. ED50 = ED50 - is a hybrid parameter (PK and PD) - is not a genuine PD drug parameterClearance x target EC50BioavailabilityPDPKThe determination of an ED50 or any ED%

29. What is plasma clerance?Clearance is the PK parameter expressing capacity of a body (or an organ) to eliminate a drug

30. plasma clearance control internal exposure For an IV administration, Clearance is the only parameter controlling internal exposure i.e. AUC 

31. 31Application of the clearance concept for Interspecies dose extrapolation

32. 32Interspecies dose extrapolation using the clearance conceptGoal : to obtain the same exposure (AUC) for the 2 speciesDose = AUC x Cl

33. Interspecies dose extrapolation using clearanceDose species1 = Dose species2 x Cl species1Cl species2

34. Species Usual dose(mg/kg)Clearance(mL/kg/min)Computed dose(mg/kg)Human0.1714.7-Dogs0.5 - 2851Cats0.05 – 0.28.60.1What is the Morphine dose in dogs and cats

35. 35Interspecies dose extrapolation using clearance Which dose of ketoprofen in goat ? : 3 mg/kg/24 h ; Cl = 0.17L/kg/h : Cl = 0.74 L/kg/hDosegoat = 13 mg/kg

36. 36The goat has often a high drug clearance A browser not grazing with a high metabolism for an efficient first-pass effectThis enhanced metabolism is thought to be an adaptation to enable detoxification for toxic plant and has the potential to render some drugs unsuitable for use in goat.

37. A more advanced used of the clearance concept for dose extrapolation: the use of the overall extraction ratio

38. It happens that the clearance for the target species is unknown:Q: how to estimate this unknown clearance from the one of the known species ?A: by using the extraction ratio computed from the known species

39. 39HeartClearing organs (liver, kidney,…)Clbody = Q x EQ = cardiac output = 180 BW-0.19 with BW= kg et Q= ml/kg/minE = overall extraction ratioEoooPhysiological model of plasma (blood) clearance

40. 40The generic model of plasma (body) clearanceModel to interpret blood clearance Clbody = Qcardiac output x Ebody flow flow no unit°

41. 41The extraction ratio Ebody = Body clearance (blood)Cardiac output

42. 42What is the Penicillin G extraction ratio in horses cardiac output: 55 mL/kg/minextraction ratio: 15.4%body clearance 8.5mL/kg/min

43. 43Extraction ratio (ER) for antibiotics Q: what is the body clearance of cefazolin in camel?A: the cardiac output in camel x the cefazolin ERDrugsER (%)Aditoprim20Penicillin G15.4Amoxicillin10.4cephapirin18.2Cefazolin10Oxytetracycline1.2Gentamicine2Marbofloxaxin7.5Enrofloxacin6.7Sulfamethazine1

44. 44Cardiac output in mammalsIn mL per minuteBody Weight in kg

45. Plasma clearance (per minute) of cefazoline in camel (250kg BW) ECVPT-2009 45 

46. What is the dose of cefazolin in camel extrapolated from dogs Dose camel = Dose dogs x Cl camelCl dogs

47. What is a dose of cefazolin in camel ?per dayCamel Cardiac output (L per day)Horse ER

48. A more advanced used of the clearance concept for dose extrapolation: the case of hepatic cleared drug

49. 49Clearances are additiveClbody = Clrenal + Clhepatic + Clother

50. Clearance for hepatic cleared drug 

51. Model for hepatic clearance (Clh)fu : free fractionClint : intrinsic clearanceEh

52. 52Hepatic Clint : in vitroFor a low extraction drug, Km>Cfree

53. Model for hepatic clearance (Clh) for a low extraction drug fu : free fractionClint : intrinsic clearanceEh

54. Dose for an hepatic cleared drug with a low hepatic ER and a total absorptionThe plasma protein binding and metabolism activity are the major determinants for the elimination of low hepatic clearance drugs; therefore it is not expected to have a good allometric relationship with BW across species for this kind of drug

55. Dose (IV) for an hepatic cleared drug with a low or a high hepatic extraction ratio (ER)The plasma protein binding and metabolism activity are the major determinants for the elimination of low hepatic clearance drugs; therefore it is not expected to have a good allometric relationship with BW across species for this kind of drugLow ERHigh ERBecause hepatic blood flow is shown to have an allometric relationship with BW, it is expected that the elimination of high hepatic clearance drug can show an allometric relationship with BW

56. Principles of doses extrapolation when clearance is not known in the target species but is known in several other species: the allometric approach

57. 57AllometryAllometry (a term coined by Huxley & Tessier 1936) is the study of size and its consequences

58. 58Range of body size in mammalsBlue whale: >108 gShrew 2 g Allometry is the study of size and its consequencesInterspecies allometric scaling is based on the assumption that there are anatomical, physiological and biochemical similarities among animals which can be described by simple mathematical models

59. 59Many allometric relationships have been established between body size and organ weight as well as body size and physiological process

60. 60Cardiac output in mammalsIn mL per minuteBody Weight in kg

61. ECVPT-2009 61The allometric approachempirical method of extrapolation based on the underlying anatomical, physiological and biological similarities in animalssuccessful for drugs which are highly dependent on renal clearance, hepatic blood flow or metabolic clearance by reaction other than MFO system

62. Simple allometryY=aBWb

63. The power function Y = aBWbWhere Y is the parameter of interest, BW is the body weight, a & b are the coefficient and exponent of the allometric equation respectivelyThe log transformation of this equation is represented as : log Y = log a + b x logBWLinear plot: slope=b and intercept=log Athe slope of the line (b) indicates the type of scaling relationship

64. Simple allometrylogY=log a +b log BWb=slopeY=aBWblog a is the Y-intercept

65. 65Gentamicin

66. Ampicillin

67. Oxytretracycline

68. Recent allometric dose estimates for antimicrobials68

69. 69Lack of allometric relationship for different NSAIDS in domestic species

70. Body (Plasma) BPA clearance in man is unknown and we wish to estimate it 70

71. Estimation de la clairance plasmatique par allométrie71

72. Rhesus monkey (6.56kg)Allometry: ClBPA = 32.4 mL/(kg.min)Experimental (from Doerge et al 2010) 38mL/kg/min Allometric estimation of plasma clearance in man from 6 species 0.00010.0010.010.11100.010.11101001000Body weight (kg)BPA clearance (L/min)ClBPA (L/min)=0.0390 x BW0.901472

73. ManClBPA = 24.7 mL/(kg.min) or 103L/h for a 70kg BWPrediction interval [9.3-66.0]Allometric estimation of plasma clearance in man0.00010.0010.010.11.0100.010.11101001000Body weight (kg)BPA clearance (L/min)ClBPA (L/min)=0.0440 x BW0.864573

74. 74Historically, aspirin was not (appropriately) used in veterinary medicineHistorically too expansive for large animalsThe doses recommended for small animals are too high. Such recommendations for salicylates were rather constant in veterinary pharmacology handbooks in e.g. Germany, USA, Russia and Spain from 1900 up to the 70’s.The fallacy of the allometric rule

75. 75A double log plot of salycilate half-life in different speciesBody Weight (KG)Half-life (h)

76. 76The Lloyd E. Davis’ paper on salicylate (1972)

77. 77The fallacy of allometric scaling for AspirinThe principal reason for this lack of universal applicability is that allometry deals only with size; specifically, it does not address metabolic differences among species.

78. 78The Lloyd E. Davis’ paperConclusion: “the present data indicate the futility of extrapolating dose and dosage regimens from one species to another, as has been done in the past, in the treatment of domestic animals”

79. 79The Lloyd E. Davis’ paper (1972) Introduction:“We believed that information relevant to the biotransformation and rates of disappearance from blood of several drugs in a series of large domestic animals might prove of value”

80. 80Extrapolation of bioavailability

81. ECVPT-2009 81GutLumenGut WallPortalveinTo site of measurementGut MetabolismHepatic MetabolismTo fecesFirst pass effect (oral route)LiverCYPP-Gp

82. Absorption & Bioavailability (F) wherefabs = fraction absorbed from GI lumenfg = fraction metabolized by GI tissueERH = hepatic extraction ratio, equivalent to hepatic “first pass” effect1 - F = “presystemic elimination”

83. F% = fabs x ffirst passffirst pass : fraction escaping the different first pass effectsfabs : absorbed fractionBioavailability by oral route

84. Bioavailability in man: prediction from rodents, primates & dogsFrom Grass ADDR 2002 pp433

85. Interspecies pharmacokinetic & pharmacodynamics scaling

86. Interspecies scaling of pharmacodynamic parameters Very little information is available for the prediction of pharmacodynamic (PD) parameters between animal species (and man) It is conceptually difficult to accept that the efficacy and potency of a drug as a antiparasitics will relate with body weight of the species

87. 87Interspecies scaling of pharmacodynamic parameters:The case of Ketoprofen (sKTP)Cat, goat, sheep, calf, horseEndpoints: inhibition of the synthesis of thromboxan (TXB2) and prostaglandinE2 (PGE2)No relationship between IC50 (or other PD parameters) with BW

88. ECVPT-2009 88Allometry of pharmacokinetics and pharmacodynamics of the muscle relaxant metocurine in mammals

89. ECVPT-2009 89

90. Limits of allometric scalingProspective Allometric Scaling:Does the Emperor Have Clothes?Peter L. Bonate, PhD and Danny Howard, PhDCritique of Prospective Allometric Scaling:Dose the Emperor Have Clothes?Iftekhar Mahmood, PhDRebuttal to Mahmood

91. ECVPT-2009 91For more information, consult the Mahmood’ book

92. ECVPT-2009 92Extrapolation from In vitro

93. PK/PD: in vitro vs. in vivoResponsePlasmaconcentrationBodyMedium concentrationTest systemResponseIn vivoIn vitroExtrapolation in vitro  in vivoMechanism-based PK/PD

94. Computation of the dose with point estimates (mean clearance and F%, MIC90)BP: 80 or 125MIC90=2µg/mLBioavailabilityOral :50% IM:80%9mL/Kg/hMetaphylaxis: 2.88mg/kgcurative: 2.81 mg/kg

95. Computation of the dose using Monte Carlo simulation(Point estimates are replaced by distributions)Dose to POC=0.9BPmetaphylaxisLog normal distribution: 9±2.07 mL/Kg/h Uniform distribution: 0.3-0.70Observed distribution

96. ECVPT-2009 96The tick blood meal: From a living animal or from a silicone membrane? Cumulative mortality of Ixodes ricinus females feeding on bovine blood through a silicone membrane with dimethylsulfoxide (DMSO) added (placebo) and with increasing doses of fipronil in DMSO.

97. ECVPT-2009 97Fipronil dose in sheep In vitro efficacious concentration : about 100 ng/mL over 7 daysPlasma clearance : about 2 mL/kg/minDose : 288 µg/kg/Day

98. Blood or plasma concentration?For hematophagous parasites: blood?For non hematophagous parasites: plasma

99. 1/27/2018Physiologically based pharmacokinetic model (PBPK)

100. 1/27/2018Physiological modelling approach: more advanced modelsPrinciplesincorporation into the kinetic structure of the model physiological events (blood flow, distribution and elimination from individual organs)Fick's law of mass balanceMore realistic than compartmental model

101.

102. ECVPT-2009 102

103. 1/27/2018PBPK modelLungAdiposeBoneBrainHeartKidneyMuscleLiverSkinVenous bloodArterial bloodBolus doses or infusionsQLungQLungQAdiposeQAdiposeQBoneQBoneQBrainQBrainQHeartQHeartQKidneyQKidneyQMuscleQMuscleQLiverQLiverQSkinQSkinQSpleenQliver arteryQGutSpleenGutClHepatic

104.

105. PBPK: applicationsToxicology predictions/extrapolations/risk analysisDrug discovery / development early ADMET Clinical / pharmacologyVeterinary medicine

106. PBPK modelsAdvantagesmore realistic than compartmental modelsoffer an interpretation of the dataDisadvantagesdifficult to accurately determine physiological and anatomical parameterscomplexity / assumptions / buildingrequires rich data (identifiability, estimability)difficult to verify and to testexpensive, time consuming

107. 1/27/2018PBPK model: toxicologyPredictive risk assessment of chemical exposuretarget tissue dosimetry: solvent, herbicide,…Extrapolationsbetween species: rodents  humanbetween doses : high (toxicology) low (NOEL)exposure scenari

108. 1/27/2018PBPK : veterinary medicineSkin disposition in swine (Riviere, 1988)Ivermectin in cattle (Laffont, 2002)Prediction of tissue residue (Law, 1999; Craigmill, 2003 ; Chapel, 2003)

109. PBPK model of OTCCraigmill, 2003

110. Extrapolation of MRLsECVPT-2009 110

111. Extrapolation of MRLs Note for Guidance EMEA/CVMP/187/00Extrapolation from major to minor species:Species for which MRLs have been set Extrapolations to: Major ruminant All ruminants Major ruminant milkAll ruminant milk Major monogastric mammal Extrapolation to all monogastric mammals Chicken and eggs Poultry and poultry eggs SalmonidaeAll fin fish Either a major ruminant or a major monogastric mammal Horses

112. Extrapolation of MRLs If identical or similar MRLs were derived in cattle (or sheep), pigs and chicken (or poultry), MRLs can be extrapolated to all food‑producing species

113. Extrapolation of MRLs Rationale:Cattle (or sheep), pigs and chicken (or poultry represent major species with different metabolic capacities and tissue compositionaccording to extrapolation principles same MRLs can also be set for ovine, equidae and rabbits, i.e. an extrapolation is possible to all food producing animals except fishConsidering the CVMP guideline on the establishment of MRLs for Salmonidae and other fin fish, then also extrapolation to all food-producing animals incl. fish possible (provided that parent compound is acceptable as marker residue in fish)Data for extrapolations to minor species: - confirmation of marker residue - proof of applicability of analytical method

114.