Learning Outcomes. Overall Picture. Part 1 Overview of Key Concepts of Clinical Pharmacokine2cs 4/23/14. A- Awaisu- A- Nader- CPPD

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1 Learning Outcomes CPPD #7 Clinical Pharmacokine2cs: Concepts and Prac2ce Applica2ons Ahmed Nader, Ph.D, BCPS Ahmed Awaisu, Ph.D, B.Pharm Upon comple;on of this session, audience are expected to be able to: 1. Describe the importance of clinical pharmacokine;cs in op;miza;on of pa;ent drug therapy. 2. Predict the effects of drug clearance, distribu;on, and bioavailability on overall plasma exposure. 3. Describe aminoglycosides, vancomycin, digoxin, and phenytoin pharmacokine;c proper;es and how they affect plasma exposure. 4. Iden;fy indica;ons for therapeu;c drug monitoring of aminoglycosides, vancomycin, digoxin, and phenytoin. 5. Recommend ini;al doses as well as specific dosage adjustments to op;mize therapy with aminoglycosides, vancomycin, digoxin, and phenytoin in specific pa;ent cases. 2 Overall Picture Part 1 Overview of Key Concepts of Clinical Pharmacokine2cs Pharmacokine2cs (PK) Drug Administered ADME Drug ConcentraGon in Plasma Pharmacodynamics Pharmacodynamics (PD) (PD) Drug ConcentraGon at Site of AcGon Drug Effect 4 A- Awaisu- A- Nader- CPPD

2 Key PharmacokineGc Concepts Compartmental Models (1- comp, 2- comp) Bioavailability (F) DistribuGon (V d ) Clearance (CL) Compartmental Models Body viewed as compartments Most commonly one or two (+ GIT) Oral Dose GIT Half- life (t 1/2 ) Abs. MulGple Dosing and IV Infusion (SS) IV Dose Central Comp. Dist. Peripheral Comp. Elim. 5 6 Compartmental Models Why is it important??? DistribuGon: V d Volume of fluid into which the drug is distributed V d =Dose/Cp 0 Digoxin Called Apparent Volume of DistribuGon because it is back- calculated from plasma concentragon E.g. Digoxin V d = 7L/kg Larger volume needs higher doses and vice verse Volume of distribu;on and dosing usually linked to body weight (L/kg and mg/kg) 7 8 A- Awaisu- A- Nader- CPPD

3 Clearance Process of effecgve removal of the drug from the body Volume of blood cleared of the drug per unit Gme (L/ hr) Unlike eliminagon rate: Amount of drug cleared from the body per unit Gme Elim. Rate = CL x Cp CL is addigve (hepagc, renal, others) EsGmaGng V d and CL V d esgmated from Dose and Cp V d = Dose / Cp 0 CL esgmated from Dose and AUC CL = Dose / AUC 9 10 Bioavailability (F) F is the frac2on of the given dose that becomes available for the systemic circulagon AbsorpGon: Rate and Extent F = F a x F g x F h Loss into feces Gut wall metabolism HepaGc metabolism Rowland M., Tozer T.: Clinical Pharmacokine;cs: Concepts and Applica;ons. 11 Curry S., Whelpton R.: Drug DisposiGon and QU CPH PharmacokineGcs - CPPD From Principles to ApplicaGons A- Awaisu- A- Nader- CPPD

4 RelaGonships: CL, V d, t 1/2 t 1/2 = (0.693*V d )/CL IV Infusion Used to achieve constant drug concentragon in plasma t 1/2 is inversely proporgonal to CL t 1/2 is directly proporgonal to V d Changes in t 1/2 can be due to changes in either CL or V d CL and V d are independent C ss depends on infusion rate and clearance t ss = depends only on t 1/2 ( 4-6 half- lives) IV Infusion IV Infusion - LD LD = Cp ss, desired * V d The larger the V d, the larger the LD Need for LD depends on half- life and condigon hip:// A- Awaisu- A- Nader- CPPD

5 MulGple Dosing MulGple Dosing Used for dosing in chronic condigons Designed to achieve constant concentragon range within the therapeugc window Results in fluctuagon of drug concentragon Governed by dose (D) and dosing frequency (Ʈ) Cp ss, max = K 0 / k e * V d * [(1-e -k e Ƭ ) / (1-e -k e t )] Cp ss, min = Cp ss, max *e -k e Ƭ hip:// Part 2 Aminoglycosides Pharmacokine2cs and Therapeu2c Drug Monitoring AG s: Need for TDM Concentration-dependent killing Concentration-dependent toxicity Peak and trough concentrations associated with efficacy and safety, respectively Dose adjustments are based on measured serum concentrations Monitored at steady state with frequency dependent on clinical judgment (once weekly for stable patients) 20 A- Awaisu- A- Nader- CPPD

6 AG s: Pharmacokinetics IV is administered as min infusion AG s: Pharmacokinetics Follows a two-comp model with a distribution phase of ~ 30 min after the end of infusion Traditionally dosed three times daily but the entire daily dose can be given once daily based on o Concentration-dependent killing o Post-antibiotic effect 21 Peak serum concentrations should not be measured until the end of the distribution phase Peak serum concentrations are measured at the end of the 1-hour infusion or 30 min after a 30-min infusion Almost exclusively (> 90%) eliminated through renal excretion Half-life is ~2 hours in adults with normal kidney function (50 hrs in RF, 3-4 hrs in hemodialysis, 36 hrs in peritoneal dialysis) V d = 0.26 L/kg 22 AG s: Pharmacokinetics AG s: Pharmacokinetics V d = 0.26 * [IBW+0.4*(TBW-IBW)] k e = ( * CrCl) A- Awaisu- A- Nader- CPPD

7 AG s: Therapeutic Range AG s: Initial Dosing Therapeutic steady state peak concentrations for gentamicin, tobramycin, and netilmicin are generally 5 10 mg/l for gram-negative infections Therapeutic peak concentrations for amikacin are mg/l Trough steady state concentrations (predose or within 30 minutes of the next dose) above 2 3 mg/l for tobramycin, gentamicin, or netilmicin or 10 mg/l for amikacin predispose patients to an increased risk of nephrotoxicity Literature-Based Dosing Recommended doses for conventional dosing in patients with normal renal function: o 3 5 mg/kg/d for gentamicin and tobramycin o 4 6 mg/kg/d for netilmicin o 15 mg/kg/d for amikacin Extended-interval doses for patients with normal renal function: o 4 7 mg/kg/d for gentamicin, tobramycin, or netilmicin o mg/kg/d for amikacin 2. Pharmacokinetic Dosing Method 3. Nomograms 26 AG s: Initial Dosing 2. Pharmacokinetic Dosing Method: 1. k e Estimate: k e = ( * CrCl) AG s: Initial Dosing 2. Pharmacokinetic Dosing Method: 4. Dosing Regimen (Intermittent Infusion): Ƭ = [ln (Cp ss, max / Cp ss, min ) / k e ] + t 2. V d Estimate: V d = 0.26 L/kg (Obesity!!) K 0 = Cp ss, max * k e * V d * [(1-e -k e Ƭ ) / (1-e -k e t )] 3. Select Cp ss Desired: LD = K 0 / (1-e -k e Ƭ ) A- Awaisu- A- Nader- CPPD

8 AG s: Initial Dosing 3. Hull and Sarubbi Nomogram (LD): AG s: Initial Dosing 3. Hull and Sarubbi Nomogram (MD): AG s: Dosing Adjustments 1. Sawchuk-Zaske Method (Peak and Trough): AG s: Dosing Adjustments 2. Sawchuk-Zaske Method (Two post-dose conc): A- Awaisu- A- Nader- CPPD

9 Part 3 Vancomycin Pharmacokine2cs and Therapeu2c Drug Monitoring Vancomycin: Need for TDM Time-dependent killing related mainly to AUC/MIC Concentration-dependent toxicity Trough concentrations associated with efficacy and safety Dose adjustments are based on measured serum trough concentrations Monitored at steady state with frequency dependent on clinical judgment (once weekly for stable patients) 34 Vancomycin: Pharmacokinetics Vancomycin: Pharmacokinetics Given as a 1-hour infusion Eliminated mainly through renal excretion 2-comp model with 30 min distribution phase Disease State Half-Life V d Adult, normal renal function 8 hrs (7 9 hrs) 0.7 L/kg ( L/kg) Adult, renal failure 130 hrs ( hrs) 0.7 L/kg Half-life = 8 hours (130 hrs in RF) Burns (Inc. BMR and GFR) 4 hrs 0.7 L/kg V d = 0.7 L/kg Peak concentrations are not strongly associated with bacterial killing (timedependent) Obesity (>30% over IBW) with normal renal function 3 4 hrs (Inc. CL due to kidney hypertrophy) V = 0.7 * IBW A- Awaisu- A- Nader- CPPD

10 Vancomycin: Therapeutic Range Average vancomycin MICs for Staph aureus and Staph epidermidis are 1 2 mg/l o o Minimum predose or trough SS concentrations equal to mg/l are usually adequate to resolve infections with susceptible organisms. MRSA with MICs of mg/l may require higher steady-state trough concentrations to achieve a clinical cure (leads to the expansion of therapeutic trough concentration range to mg/l) Vancomycin: Therapeutic Range Since vancomycin exhibits time-dependent killing, microbiolgic or clinical cure rates are not closely associated with peak serum concentrations However, ototoxicity has been reported when vancomycin serum concentrations exceed 80 mg/l, so the therapeutic range for steady-state peak concentrations is usually considered to be mg/l Trough SS concentrations above mg/l are associated with increased incidence of nephrotoxicity Vancomycin: Initial Dosing 1. Literature-Based Dosing IDSA Guidelines: Recommended dose for vancomycin in patients with normal renal function is mg/kg given every 8 or 12 hrs Vancomycin: Initial Dosing 2. Pharmacokinetic Dosing Method: 1. Clearance Estimate: Cl (ml/min/kg) = 0.695*(CrCl) o Q8 versus Q12??? 2. V d Estimate: 2. Pharmacokinetic Dosing Method 3. Nomograms 3. Select Cp ss desired: V d = 0.7 L/kg Cp ss, min : mg/l (sometimes up to 20 mg/l) A- Awaisu- A- Nader- CPPD

11 Vancomycin: Initial Dosing 2. Pharmacokinetic Dosing Method: Vancomycin: Initial Dosing 3. Moellering Nomogram: 4. Dosing Regimen: LD = Cp ss, max * V d MD = Cp ss, max * V d * (1-e -kƭ ) Ƭ = ln (Cp ss, max / Cp ss, min ) / k Vancomycin: Dosing Adjustments 1. Direct Linear Method: D new /C ss,new = D old /C ss,old 2. Trough-Only Method: Part 4 Digoxin Pharmacokine2cs and Therapeu2c Drug Monitoring Ƭ new = (C ss trough,old / C ss trough,new ) * Ƭ old Same original dose and new interval rounded to practical values Ahmed Awaisu, Ph.D, BPharm 43 A- Awaisu- A- Nader- CPPD

12 Key Resources... Digoxin: Synopsis Control symptoms in CHF (positive inotropic effect) Ventricular rate control in AF (negative chonotropic effect) LD of mg per 70kg is administered for digitalization MD of 0.25 mg/day (range mg) in patients with normal renal function Has a relatively long t 1/2 ( days) Use of clinical pharmacokinetics to adjust dosing regimen decrease the incidence of digoxin toxicity 45 Digoxin: Indications for TDM Suspected digoxin toxicity (GI, CNS, CVS) Suspected drug interaction Clinical deterioration after initial good response Marked alteration in renal function Assess compliance Conditions known to alter response or PK Digoxin: Clinical Pharmacokinetics Absorption is rather passive from the duodenum and upper jejunum Degree of absorption depends on dosage form as well as concomitant medications Oral F, though somewhat variable, reported to be 70%=tabs, 85%=elixir, 95%=caps, 80%=im Literature reports serum digoxin concentration on the order of % in patients simultaneously receiving erythromycin or TCN 47 A- Awaisu- A- Nader- CPPD

13 Digoxin: Clinical Pharmacokinetics Follows 2-compartment model with a long distribution phase V d for digoxin is very large: 7-8L/kg ( 7.3L/kg) V d (L) = (3.8L/kg) (wt in kg) (Cl cr in ml/min) Digoxin shows little affinity for distribution into fat; consequently dosing should be based on IBW It is 20 25% plasma protein-bound Decline in renal function V d to 65% Hyperthyroidism V d ; Hypothyroidism V d Digoxin: Clinical Pharmacokinetics Excreted predominantly by the renal route o 60-80% excreted unchanged by GF and active tubular secretion Renal disease substantially alters the t 1/2 of digoxin Reported t 1/2 in patients with normal renal function is 1.5 days Reported t 1/2 in anephric patients? Digoxin clearance (Cl) varies considerably among individuals and should be estimated for each patient Cl t = Cl m + Cl r Digoxin: Clinical Pharmacokinetics 1 Koup s Equation: o Without CHF Cl dgx = Cl cr ml/min + 40 o With CHF Cl dgx = Cl cr ml/min + 20 Digoxin: Clinical Pharmacokinetics 2 Sheiner s Equation: Cl digoxin (ml/min) without CHF = (0.8 ml/kg/min) (wt in kg) + Cl cr ml/min Cl digoxin (ml/min) with CHF = (0.33 ml/kg/min) (wt in kg) (Cl cr ml/min) A- Awaisu- A- Nader- CPPD

14 Digoxin: Therapeutic and Toxic Plasma Concentration Considerable inter- and intra-patient variation in pharmacodynamic response to digoxin TR: µg/l (ng/ml) o Inotropic effect: ng/ml o Chonotropic effect: up to 2.0 ng/ml Due to the variability, clinicians should consider these TRs as initial guidelines Digoxin: Therapeutic and Toxic Plasma Concentration Steady state concentration > 2 ng/ml associated with ADRs At 2.5 ng/ml, half of all patients exhibit some form of digoxin toxicity: o GIT (anorexia, N, V, D, abdominal pain) o CNS (headache, fatigue, insomnia, vertigo) o CVS (2 nd or 3 rd degree AV block, bradycardia, ventricular tachycardia, PVC) o Visual disturbances (blurred vision, changes in color) Digoxin: Therapeutic and Toxic Plasma Concentration Has long distribution phase: 8 12 hrs Serum concentration should not be measured until the distribution is completed When the serum concentration is very high but the patient is not exhibiting any symptoms of digitalis overdose, consideration should be given to the possibility of blood sampling during distributive phase Digoxin: Dosage Regimen Design 1. Literature-Based Dosing Method 2. Pharmacokinetic Dosing Method 3. Dosing Nomograms 56 A- Awaisu- A- Nader- CPPD

15 Digoxin: Dosage Regimen Design LD = V d C p / S F MD = Cl digoxin C pss-aver τ /S F V d (L) = (3.8L/kg) (wt in kg) (Cl cr ml/min) Cl dgx (ml/min ) = Cl cr + Cl m Cl = K e V d t 1/2 = 0.693/K e K e = ln (C 0 /C)/t t 0 o In obese subjects, Cl cr and Cl dig are calculated using IBW Digoxin: Dosage Regimen Design Steps for Initial Dosage Regimen Design 1. Estimate the Cl cr : Cockroft Gault equation 2. Calculate Digoxin Cl: Koup s or Sheiner s equation o Cl dgx = Cl cr ml/min + 40 (if no CHF) 3. Estimate V d : Individualized V d (preferred) o Population: V d = 7 L/kg o Individualized: V d = (3.8L/kg) (wt in kg) (Clcr) Digoxin: Dosage Regimen Design Steps for Initial Dosage Regimen Design 4. Determine the desired C pss : o CHF: ng/ml o AF: ng/ml 5. Calculate Dose: LD and MD as below: o LD = V d C pss / S F o MD = Cl digoxin C pss τ /S F o LD is given as 50% initially then 25% after 6 hours and 25% after another 6 hours 6. Round calculated dose: Tab.125 µg and 250 µg Digoxin: Dosage Regimen Design Dose Alteration Digoxin follows linear dose-proportional PK D new = Cp Cp ss, new *D ss,old Requires achievement of steady-state (5 t 1/2 ) in order to be applied If dose change is not enough to achieve the desired concentration, dosage interval should also be changed. old A- Awaisu- A- Nader- CPPD

16 Digoxin: Sampling Time Samples for routine digoxin monitoring are taken 7 14 days after a MD is initiated or changed In ESRD it may take days Once steady state has been reached, plasma samples should be drawn just before the next dose (trough levels) Any sampling time that avoids the distribution phase (at least 4-6 hours post IV or 6-8 hours post oral) is acceptable Digoxin: Summary of PK Parameters PK Parameter Value Therapeutic Range µg/l (ng/ml) Half-life (t 1/2 ) hours Salt Form (S) 1.0 Bioavailability (F) o 70% (Tablets) o 80-85% (Elixir) o % (Soft-gelatin) o 80% (I.m.) Digoxin: Summary of PK Parameters Digoxin: Dosage Regimen Design PK Parameter Volume of Distribution (V d ) Value 7 8 L/Kg 3.8L/kg (weight) (Clcr) Cl (ml/min) Cl cr ml/min + 40 Cl (ml/min) in CHF Cl cr ml/min + 20 t max mins 64 A- Awaisu- A- Nader- CPPD

17 Practice Experience A 62-year-old, 50 kg female patient, taking 0.25 mg digoxin was admitted due to? digoxin toxicity. SrCr = 240 µmol/l; serum digoxin conc = 5 ng/ml 1. What will be your recommendation as a TDM pharmacist? 2. Find the time for the concentration to drop to a safe level of ng/ml. 3. Calculate the dose if to maintain Css aver of 1.5 ng/ml. Practice Experience JB is a 42-year-old male patient weighing 56 kg admitted to PGH on 22 July 2003 with CC of dyspnea, chest pain, and easy fatigability. He is a long standing CHF patient with AF. Medications include captopril, frusemide, Slow- K, warfarin, and digoxin. O/E he has left-leg cellulitis for which he was placed on oral amoxycillin. Digoxin therapy was started since 1997 and is currently on MD of 0.25 mg OD. Serum creatinine concentration was 90 µmol/l and measured digoxin from TDM lab. on day of admission was 0.29 ng/ml. Determine compliance to digoxin therapy in this patient. Practice Experience Digoxin was continued throughout his stay in the ward at 0.25 mg daily (starting from 23 July 2003). Spironolactone was added and another sample taken on 02 Aug The level was 2.72 ng/ml. Explain whether the drug has reached steady state or not by 23 July 2003 and by 02 Aug Part 5 Phenytoin Pharmacokine2cs and Therapeu2c Drug Monitoring Ahmed Awaisu, Ph.D, BPharm A- Awaisu- A- Nader- CPPD

18 Phenytoin: Synopsis Used primarily as an antiepileptic agent: o chronic treatment of tonic-clonic seizures and partial seizures o acute treatment of status epilepticus Treatment of trigeminal neuralgia Major issues: o Binding of PHT to plasma protein is decreased in patients with renal failure or hypoalbuminemia o The metabolic capacity for PHT is limited (saturable) o Steady state concentration changes in a disproportionate fashion after dose is altered Phenytoin: Synopsis AB receives phenytoin 200mg PO daily. PHT steady state serum concentration was measured as 10 mg/ L. The neurologist wishes to increase the dose to 300mg PO daily for control of seizures. What will be the new serum concentration at steady state? 70 Phenytoin: Indication for TDM Suspected phenytoin toxicity (nystagmus, ataxia) Suspected drug interaction Uncontrolled seizures Assessment of compliance Conditions known to alter response or PK Phenytoin: Clinical Pharmacokinetics Completely absorbed (F = 1.0) Injectable/capsule consist of sodium salt (S = 0.92) Chewable tab. and susp. contain acid form (S = 1.0) PO: Peak concentration time at 3 to 12 hours Bioavailability reduced: o Rapid gastrointestinal transit times. o Receiving liquid dietary supplement (NG feeding) Fosphenytoin: a prodrug of PHT converted rapidly invivo 71 A- Awaisu- A- Nader- CPPD

19 Phenytoin: Clinical Pharmacokinetics Approximately 90% of PHT bound to serum albumin 10% is unbound and free to equilibrate with the tissues Rate of metabolism (and/or excretion) is proportional to the plasma concentration. Concentration t ½ (hours) Phenytoin: Clinical Pharmacokinetics Eliminated primarily (>95%) through hepatic metabolism via CYP2C9 Obeys Michaelis-Menten or saturable non-linear PK Phenytoin: Clinical Pharmacokinetics PHT s clearance is determined by the equation below: max CL = V Km + Cpss V max is the maximum rate of metabolism K m is the drug concentration that results in half the maximal metabolic rate Phenytoin: Clinical Pharmacokinetics Drug Interactions Interaction with VPA (displacement and inhibition of CYP450) Phenytoin displaced from binding sites Reduced (~50%) total concentration Increased ( %) of the unbound PHT A- Awaisu- A- Nader- CPPD

20 Phenytoin: Therapeutic and Toxic Plasma Concentration TR: mg/l Nystagmus (>20mg/L) Ataxia (>30mg/L) Diminished mental capacity, encephalopathy (>40mg/L) Gingival hyperplasia, folate deficiency, peripheral neuropathy Phenytoin: Therapeutic and Toxic Plasma Concentration Hypoalbuminemia Correction Hypoalbuminemia: C adjusted = C measured / (Albumin* ) Renal Failure: C adjusted = C measured / (Albumin* ) Phenytoin: Dosage Regimen Design 1. Literature-Based Dosing Method 2. Pharmacokinetic Dosing Method 3. Nomogram and Orbit Graph Phenytoin: Dosage Regimen Design 1. Literature-Based Dosing Method Doses aimed to achieve concentrations of mg/l LD: mg/kg MD: 4-6 mg/kd/d (adults) MD: 5-10 mg/kd/d (children < 16yrs) A- Awaisu- A- Nader- CPPD

21 Phenytoin: Dosage Regimen Design 2. Pharmacokinetic Dosing Method 1) Determine the K m and V m : 1) K m = 4 mg/l (< 16 yrs: 6 mg/l) 2) V max = 7 mg/kg/d (< 6yrs: 12 mg/kg/d, 7-16 yrs: 9 mg/kg/d) 2) Determine the V d : 1) 0.7 L/kg in non-obese patients with normal protein binding 2) Obese patients: V d = 0.7 * [IBW (TBW IBW)] Phenytoin: Dosage Regimen Design 2. Pharmacokinetic Dosing Method 3) Determine the LD: 4) Determine the MD: C LD = V S pss* Dosing Rate ( d D ) τ V = S(K max m *C + C pss pss ) Phenytoin: Dosage Regimen Design 2. Pharmacokinetic Dosing Method Phenytoin: Summary of PK Parameters PK Parameter Value Therapeutic Range mg/l Salt Form (S) 0.92 (Tablet/Suspension) Bioavailability (F) 1.0 Volume of distribution 0.7 L/kg Clearance V max = 7.2 mg/kg/day K m = 4.4 mg/l A- Awaisu- A- Nader- CPPD

22 Phenytoin: Dosage Regimen Design R o, V m What Else Can We Say? C p K m References... Bauer LE. Applied Clinical Pharmacokinetics. 2 nd ed. McGraw-Hill, QuesGons/Comments Winter ME. Basic Clinical Pharmacokinetics. 5 th ed. LWWW, Rybak M, Lomaestro B, Rotschafer JC et al. Therapeutic monitoring of vancomycin in adult patients: A consensus review of the ASHP, the IDSA, and the Society of Infectious Diseases Pharmacists. Am J Health-Syst Pharm. 2009; 66: A- Awaisu- A- Nader- CPPD