TDM of Drugs with Non-Linear* Pharmacokinetics

TDM of drugs with non-linear* pharmacokinetics

*aka “saturable” or “zero order”

David A Joyce ANZ TDM Symposium, May 2015 Determination of percentage of alcohol at material time 71. (1) In any proceeding such as is mentioned in section 70 (1), the percentage of alcohol present in the blood of a person at any time which is or may be material in the proceeding shall be calculated having regard to that time, the time of the person's last drink containing alcohol taken at or before the time which is or may be material in the proceeding, and the time at which the sample of the person's breath or blood was provided or taken for analysis, by varying the analysis result referred to in section 68 or section 69 by such amount, if any, necessary to give effect to the presumption that the percentage of alcohol in the blood of a person increases at the rate of 0.016 per centum per hour for a period of 2 hours after his latest drink containing alcohol and, after that period, decreases at the rate of 0.016 per centum per hour. 0.16 0.14 0.12 0.10 0.08 0.06

[Ethanol] % [Ethanol] 0.04 C = C e (–ke*t) 0.02 0 0.00 0 1 2 3 4 5 6 7 8hr 0.35 0.3 0.295% at 11:10hr 0.25 0.2 0.15 0.123%

[Ethanol ] % 0.1 at 20:35hr 0.05 0 9:00:00 12:00:00 15:00:00 18:00:00 21:00:00 Time (hr)

29 YO male pedestrian 70 0.295% 60 at 11:10hr 50 40 30 0.123% 20 at 20:35hr [Ethanol] mM 10 0 9:00:00 12:00:00 15:00:00 18:00:00 21:00:00 Time (hr)

Alcohol dehydrogenase CYP1E2 [Ethanol] Enzyme Saturation % 2 100 10 4 60 9 5 3 8 7 0 0 0 0 0 0 0 0.05 0.10 Km=0.015% V = V Vm 0.15 * 0.20 [ Alc [ Alc ]+Km 0.25 ] 0.30%

Elimination Rate (% of Max) 100 10 20 30 40 50 60 70 80 90 0 0 Vm Biopharmac WagnerJ JG 5 ~0.018% 10 [Drug] 1973;1:103 Pharmacokin 15 20 - 121 25 [Ethanol] Enzyme Saturation % 2 100 10 4 60 9 3 5 8 7 0 0 0 0 0 0 0 V = V 0.05 Vm First order Alc   0.10 * t Alc [ Alc t [ = = Alc Alc = ]+Km 0.15 - ]   Alc Zero order kAlc Alc t 0 e t 0.20 ( = = Alc - = kt - ) k 0.25 0 - kt 0.30% % % hr hr 0.35

0.3 0.295% at 11:10hr 0.25 0.2 0.15 0.123% 0.1 Km = 0.015% [Ethanol ] % Vm = 0.0175%/hr at 20:35hr 0.05 0 9:00:00 12:00:00 15:00:00 18:00:00 21:00:00 Time (hr)

29 YO male pedestrian Common, monitored drugs with zero-order kinetics within or below therapeutic range.

Alcohol Phenytoin Perhexiline Methotrexate Voriconazole Phenytoin

CYP2C9 - Polymorphic - Interactions OH - Saturable OH

2003 (Male, Age 69): Phenytoin for seizures  phenytoin toxicity Accused of public drunkenness 1 1 Unstable [phenytoin] on 90mg/day ( /4 – /3 usual dose) 2008 (Age 74): Warfarin for recurrent TIA  INR > 10 after loading dose Restarted after INR returned to 2, at 0.5mg o.d. Abandoned when INR returned to >10

Clin Pharm consult  CYP2C9 & VKORC1 genotyping

CYP2C9 PROMOTER CODING REGION 3’UTR

*2* *3* Genotype Phenotype Average Warfarin Dose *1/*1 (wt/wt) Rapid metaboliser 5.6mg *1/*2 or *1/*3 Intermediate metaboliser 3.2 - 4.9mg *3/*3 Poor metaboliser 1.6mg

Lehmann et al., J Clin Pharmacol 2003;43:136. Higashi et al., JAMA 2002;287:1690 Principle

A variant enzyme (CYP2C9 in this example) may transform a conventional dose to a saturating one

Anticipate by genotyping? Dose adjustment: First Order vs Zero Order Elimination

First Order: Fall in concentration (C) over any moment (t):

C/t = Ct * ke

12 C(0-1)/C0*Vd = CL 10 Vd*ke = CL 8

6 CL = D [Drug] 4 AUC

2 D1 = Cmax1 = Ct1 = AUC1 D Cmax Ct AUC 0 2 2 2 2 0 10 20 30 Time (hr) D D 1 = 2 = CL AUC1 AUC2

IE, provided CL remains constant, concentration at any time  dose (“linearity”) C/C0*Vd = CL C/10*Vd = CL C/9*Vd = CL  Zero Order C/8*Vd = CL elimination CL changing!

Time

70 Zero Order 60 50 C  dose 40 30 20 First Order 10 0 Drug Concentration in plasma in Concentration Drug 0 5 10 15 20 25 Dose Principle

The dose change needed to reach a new target concentration is less than proportional

Measure & Correct Anti-anginal drug, blocking CPT-1-mediated fatty acid Perhexiline uptake to mitochondrial oxidative metabolism; Hepatotoxic, neurotoxic, concentration-dependent 74 yo woman. Severe stable angina. Nitrates, -adrenergic blocker, nicorandil Perhexiline, 200mg daily (same >1 year)

OH CYP2D6-mediated hydroxylation -Polymorphic (>20-fold dosage range) -Saturable -Open to interactions -Px-OH/Px ratio 3 days after loading predicts phenotype

N CH2CH H ”If facilities for determining plasma levels are not available, Pexsig should not be prescribed” (Approved Product Information)

Sallustio BC, Westley IS, Morris RG. Br J Clin Pharmacol. 2002;54:107 Perhexiline 74 yo woman. Severe stable angina. Nitrates, -adrenergic blocker, nicorandil Perhexiline, 200mg daily (same >1 year) Extensive metaboliser, probably (ratio 1.1) Date Perhexiline OH-perhexiline Ratio ALT  x 5 GT  x 12 600-1200ug/L Alk Phos  x 2 30 Mar 580 ug/L 633 ug/L 1.1

13 Jul 2563 2080 0.8 Perhexiline stopped 27 Jul 2617 2245 0.9 Charcoal 10 Aug 2444 2542 1.0

24 Aug 1038 1134 1.1

Why? Ondansetron, prochlorperazine started for nausea Competition interaction for saturable enzyme Principle

Competition interactions can be dramatic when the elimination system approaches saturation

Measure & Correct Other drugs with zero-order elimination within or above therapeutic range?

“Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg/day “ (Product Information)

CYP2D6 Venlafaxine O-desmethylvenlafaxine

Therapeutic range, venlafaxine + desmethylvenlafaxine: 150 – 750 ug/L, pre-dose 500 600 ug/L Venlafaxine ug/L O-desmethylvenlafaxine 500 400 1200 400 300 750 900 300 200 450 200 225 100 100

0 0 0 200 400 600 800 1000 1200 mg 0 200 400 600 800 1000 1200mg 4

2 Ratio

Metabolite/Parent 0 0 200 400 600 800 1000 1200 mg Saturating CYP2D6 elimination Principle

Zero-order elimination may exist unsuspected at drug concentrations above conventional ranges Transport pathways can saturate too.

Posaconazole: Saturable absorption  Less than proportional dose – concentration relationship

Methotrexate: Saturable absorption Saturable tissue transport Saturable renal tubule transport  Very complex!  transport Saturable renal tubule Saturable tissue transport Saturable absorption Methotrexate Very complex!

Availability (%) 2 100 10 4 60 9 3 5 8 7 0 0 0 0 0 0 0 20 40 Dose Dose (mg/M 1987;110:788 Teresi 60 et al. J 80 2 Pediatrics )] - 92 100 Principle

Zero-order processes may exist throughout absorption, distribution, metabolism & elimination Summary A variant enzyme (eg.CYP2C9 may transform a conventional dose to a saturating one The dose change needed to reach a new target concentration is less than proportional Competition interactions can be dramatic when elimination approaches saturation Zero-order elimination may exist unsuspected at drug concentrations above usual ranges Zero-order processes may exist in absorption, distribution, metabolism & elimination Measure & Correct!