Pharmacokinetics Refresher PDF

Pharmacokinetics: A Refresher Patient Cases 1. H.R. is receiving vancomycin for methicillin-resistant Staphylococcus aureus bacteremia. H.R. has chronic kidney disease. A 1-g intravenous dose of vancomycin is given at noon on March 21. A concentration obtained at 2:00 p.m. on March 21 is 27.8 mg/L...

Pharmacokinetics: A Refresher Patient Cases 1. H.R. is receiving vancomycin for methicillin-resistant Staphylococcus aureus bacteremia. H.R. has chronic kidney disease. A 1-g intravenous dose of vancomycin is given at noon on March 21. A concentration obtained at 2:00 p.m. on March 21 is 27.8 mg/L. After no additional doses, a concentration obtained at 2:00 p.m. on March 24 is 14.1 mg/L. If you were to give a 1-g dose at 4:00 p.m. on March 24 and your goal trough concentration to achieve an appropriate AUC/MIC ratio was 10–15 mg/L, which would be the best time to give the next dose? A. 1 day after the dose on the 24th. B. 3 days from the dose on the 24th. C. 6 days from the dose on the 24th. D. Insufficient information to calculate when to redose. 2. After the administration of 100 mg of a drug intravenously and 200 mg of the same drug by mouth, the areas under the curves (AUCs) are 50 and 25 mg*hr/L, respectively. Which best describes the bioavailability of this drug? A. 25%. B. 37.5%. C. 50%. D. 100%. I. BASIC PHARMACOKINETIC RELATIONSHIPS Table 1 contains definitions of terms. Table 1. Pharmacokinetic Term Definitions AUC AUCev AUCiv Cmax Cmin C0 Css Css avg Css max DoseEV DoseIV F k R0 τ t ti Vd Area under the curve Area under the curve after an extravascular dose Area under the curve after an intravenous dose Maximum concentration Minimum concentration Concentration at time zero Concentration at steady state Average concentration at steady state Maximum concentration at steady state Dose given extravascularly Dose given intravenously Bioavailability Elimination rate constant Rate of infusion Dosing interval Time of the intermittent infusion Time from initiation of the continuous infusion Volume of distribution ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-78 Pharmacokinetics: A Refresher A. Absorption doseiv * AUCev F = ––––––––––––– doseev * AUCiv B. Distribution Rapid intravenous (or oral) bolus: F * dose Vd = –––––––– C0 R0 Vd = –––––– k * Css R0 R0 Continuous intravenous infusion before steady state: Vd = ––––– (1– e–kti) and C = ––––– (1– e –kti) C *k Vd * k Continuous intravenous infusion at steady state: Multiple intravenous bolus at steady state: dose Vd = –––––––––––––– Css max *(1– e –kτ) Multiple intermittent intravenous infusion at steady state: R0 *(1–e –kt) Vd *k * (1– e ) Css max = ––––––––––––– –kt 1–e –kt R0 Vd = ––– * –––––––––––––––– k Cmax – (Cmin *e –kt) Css min = Css max * e -k(τ-t) C. Clearance dose AUC Clearance = ––––– Cl k = ––– Vd (1nC1 – 1nC2) k = –––––––––––– (t2 – t1) 0.693 t1/2 = ––––– k Continuous intravenous infusion at steady state: R0 Clearance = –––– Css Continuous intravenous infusion before steady state: R0 Clearance = –––– * (1 – e –kti) C Multiple intravenous (or oral) bolus at steady state: (1nC F*dose ––––––– τ Clearance = ––––––––– Css,avg – 1nC ) k max min τ = ––––––––––––––– II. ABSORPTION A. First-Pass Effect 1. Blood that perfuses almost all the gastrointestinal (GI) tissues passes through the liver by means of the hepatic portal vein. a. Fifty percent of the rectal blood supply bypasses the liver (middle and inferior hemorrhoidal veins). b. Drugs absorbed in the buccal cavity bypass the liver. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-79 AL GRAWANY Pharmacokinetics: A Refresher 2. Examples of drugs with significant first-pass effect Amitriptyline Atorvastatin Buprenorphine Buspirone Diazepam Diltiazem Doxepin Felodipine Imipramine Isosorbide dinitrate Labetalol Metoprolol Morphine Nifedipine Nitroglycerin Propafenone Propranolol Raloxifene Simvastatin Verapamil B. Enterohepatic Recirculation (Table 2) 1. Drugs are excreted through the bile into the duodenum, metabolized by the normal flora in the GI tract, and reabsorbed into the portal circulation. 2. Occurs with drugs that have biliary (hepatic) elimination and good oral absorption 3. Drug is concentrated in the gallbladder and expelled on sight, smell, or ingestion of food. Table 2. Examples of Compounds Excreted in Bile and Subject to Enterohepatic Cycling Compound Chloramphenicol Digoxin Estrogens Imipramine Indomethacin Nafcillin Rifampin Sulindac Testosterone Tiagabine Valproic acid Vitamin A Entity in Bile Glucuronide conjugate Parent Parent Parent and desmethyl metabolite Parent and glucuronide Parent Parent Glucuronides of parent and metabolites Conjugates Glucuronide conjugate Glucuronide conjugates Conjugates Patient Case 3. Which statement best describes P-glycoprotein? A. It is a plasma protein that binds basic drugs. B. It transfers drugs through the GI mucosa, increasing absorption. C. It diminishes the effect of cytochrome P450 3A4 (CYP3A4) in the GI mucosa. D. It is an efflux pump that decreases GI mucosal absorption. C. P-Glycoprotein (ABCB1) 1. P-glycoprotein is an efflux pump (located in the esophagus, stomach, and small and large intestines) that pumps drugs back into the GI lumen; it is a more important factor in drug interactions during drug absorption than intestinal CYP3A4. 2. Both CYP3A4 and P-glycoprotein are located in small intestinal enterocytes and work together to decrease the absorption of xenobiotics. 3. Most CYP3A4 substrates are also P-glycoprotein substrates. 4.  Many CYP3A4 inhibitors/inducers also inhibit/induce P-glycoprotein, leading to an increase or decrease in bioavailability. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-80 Pharmacokinetics: A Refresher Table 3. P-glycoprotein Drug Interactions Substrate Enhanced P-gp effects (decreased substrate serum concentrations) Diminished P-gp effects (increased substrate serum concentrations) Apixaban Colchicine Cyclosporine Dabigatran Digoxin Edoxaban Ranolazine Rivaroxaban Tacrolimus Carbamazepine Phenytoin Rifampin St. John’s wort Amiodarone Clarithromycin Dronedarone Erythromycin Hepatitis C direct-acting antivirals Itraconazole Ivacaftor Ketoconazole Propafenone Quinidine Ranolazine Verapamil III. DISTRIBUTION A. Apparent Vd: Proportionality constant that relates the amount of drug in the body to an observed concentration of drug B. Protein Binding (Table 4) Table 4. Common Proteins Involved in Drug Protein Binding Protein Albumin α-1-Acid glycoprotein Lipoprotein Types of Drugs Bound Acidic Basic Lipophilic and basic Molecular Weight 65,000 44,000 200,000–3,400,000 Normal Concentrations g/L mcmol/L 35–50 500–700 0.4–1.0 9–23 Variable Variable C. P-Glycoprotein 1. Functions as an efflux pump on the luminal surface of the blood-brain barrier, limiting entry to the central nervous system 2. It may be especially important with opioids: Induction of P-glycoprotein by chronic use of opioids may decrease the opioid effect (tolerance). 3. P-glycoprotein is also found in tumor cells, resulting in the efflux of chemotherapeutic agents from the cell and, ultimately, multidrug resistance. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-81 Pharmacokinetics: A Refresher IV. CLEARANCE A. Metabolic enzymes (Table 5) and transport proteins (Table 6) involved in drug clearance Table 5. Enzymes Involved in Drug Metabolism Oxygenases CYPs Monoamine oxygenases Alcohol dehydrogenases Aldehyde dehydrogenases Xanthine dehydrogenases Conjugating enzymes Uridine diphosphate–glucuronyl transferases Glutathione S-transferase Acetyltransferases Methyltransferases Hydrolytic enzymes Esterases Amidases Epoxide hydrolases Dipeptidases CYP = cytochrome P450. Table 6. Drug Transport Proteins Transport Protein Transport Protein Superfamily (Gene [Protein]) SLC SLC01A2 [OATP1A2] SLCO1B1 [OATP1B1] SLCO1B3 [OATP1B3] SLC22A1, SLC22A2, SLC22A6, SLC22A8 [OAT and OCT] SLCO2B1 [OATP2B1] SLC15A1, SLC15A2 [PEPT1, PEPT2] SLC47A1, SLC47A2 [MATE1, MATE2-K] Location and Function Drugs Affected by Transport Protein Digoxin Hepatocyte: Bile acid uptake Levofloxacin Methotrexate Statins Hepatocyte: Hepatic uptake Hepatitis C directof drugs acting antivirals Rifampin Statins Valsartan Hepatocyte: Hepatic uptake Digoxin of drugs Fexofenadine Rifampin Statins Hepatocyte: Hepatic uptake Dofetilideb of drugs Methotrexatea Renal tubule Organic anions (interstitial side): Secretion and cationsb Salicylatea of drugs Tetracyclinea Zidovudinea Hepatocyte: Hepatic uptake Fexofenadine of drugs Glyburide Statins Renal tubule Captopril Intestinal enterocytes Cephalexin Enalapril Valacyclovir Renal tubule Metformin Inhibitors of Transport Protein Naringin Clarithromycin Cyclosporine Gemfibrozil Hepatitis C direct-acting antivirals Teriflunomide Cyclosporine Erythromycin Teriflunomide Cimetidine Teriflunomide Cyclosporine Gemfibrozil Cimetidine ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-82 Pharmacokinetics: A Refresher Table 6. Drug Transport Proteins (Cont’d) Transport Protein Transport Protein Superfamily (Gene [Protein]) ABC ABCB11 [BSEP] ABCC2, 3, 4, and 5 [MRP2, 3, 4, and 5] ABCB1 [MDR1] (P-glycoprotein) ABCB4 [MDR3] ABCG2 [BCRP] a Location and Function Hepatocyte: Bile acid excretion into bile Hepatocyte: Excreting water-soluble drugs and metabolites into blood Renal tubule (luminal side): Secretion of drugs Hepatocyte: See text in handout Renal tubule (luminal side): See text in handout Hepatocyte Hepatocyte: Biliary excretion Drugs Affected by Transport Protein Pravastatin Inhibitors of Transport Protein Glucuronide, sulfate, and glutathione metabolitesa Methotrexatea Pravastatina Rifampina See text Probenecid Ritonavir Digoxin Paclitaxel Vinblastine Cladribine Daunorubicin Doxorubicin Imatinib Methotrexate Mitoxantrone Ozanimod Rosuvastatin Topotecan Itraconazole Ritonavir Amiodarone Quinidine Verapamil Omeprazole Ritonavir Teriflunomide Drugs affected by transport proteins in hepatocytes. Drugs affected by transport proteins in the renal tubule. b Patient Case 4. A renal transplant patient receiving cyclosporine is given a diagnosis of community-acquired pneumonia. The patient is admitted to the hospital and initiated on ceftriaxone and a macrolide. A physician asks you to choose a macrolide that will not interact with the patient’s cyclosporine. Which is the best choice to avoid this potential drug interaction? A. Erythromycin. B. Clarithromycin. C. Azithromycin. D. Doxycycline (because all macrolides will interact). B. Cytochrome P450 1. Introduction a. A group of heme-containing enzymes responsible for phase 1 metabolic reactions b. Characteristic absorbance of light at 450 nm (hence CYP450) c. Located primarily in the membranes of the smooth endoplasmic reticulum in the liver, small intestine, brain, lung, and kidney d. Encoded by a supergene family and subfamily; separate genes code for different isoenzymes e. Drugs generally have a high affinity for one particular CYP, but most drugs also have secondary pathways (see Table 7). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-83 Pharmacokinetics: A Refresher Table 7. CYP Drug Interactions Gene Designation Induction Inhibition CYP1A2 Carbamazepine Modafinil Nafcillin Omeprazole Rifampin CYP2C9/10 Enzalutamide Phenobarbital Phenytoin Rifampin Rifapentine CYP2C19 Carbamazepine Efavirenz Enzalutamide Phenobarbital Prednisone Rifampin St. John’s wort CYP2D6 Not an inducible enzyme Amiodarone Cimetidine Ciprofloxacin Diltiazem Efavirenz Erythromycin Fluvoxamine Mexiletine Norfloxacin Amiodarone Efavirenz Fenofibrate Fluconazole Fluvoxamine Isoniazid Lovastatin Metronidazole Paroxetine Sertraline Sulfamethoxazole Trimethoprim Voriconazole Cimetidine Esomeprazole Fluoxetine Fluvoxamine Isoniazid Ketoconazole Lansoprazole Modafinil Omeprazole Oxcarbazepine Pantoprazole Topiramate Voriconazole Amiodarone Bupropion Celecoxib Chlorpheniramine Cimetidine Cinacalcet Citalopram Diphenhydramine Duloxetine Escitalopram Fluoxetine Haloperidol Methadone Metoclopramide Midodrine Paroxetine Propafenone Quinidine Ritonavir Sertraline Terbinafine Thioridazine CYP3A4 Carbamazepine Efavirenz Enzalutamide Modafinil Nevirapine Oxcarbazepine Phenobarbital Phenytoin Amiodarone Aprepitant Atazanavir Boceprevir Cimetidine Clarithromycin Darunavir Delavirdine Diltiazem Erythromycin Fluconazole (large doses) Pioglitazone Rifabutin Rifampin Rifapentine St. John’s wort Fluvoxamine Fosamprenavir Imatinib Itraconazole Ketoconazole Nelfinavir Ritonavir Telaprevir Verapamil Voriconazole ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-84 Pharmacokinetics: A Refresher Table 7. CYP Drug Interactions (Cont’d) Gene Designation Substrates CYP1A2 Acetaminophen Amitriptyline Caffeine Clomipramine Clozapine Cyclobenzaprine Estradiol Fluvoxamine Haloperidol Imipramine Mirtazapine Olanzapine Riluzole Ropinirole R-warfarin Theophylline Zolmitriptan f. CYP2C9/10 Amitriptyline Celecoxib Diclofenac Fluoxetine Glimepiride Glipizide Glyburide Ibuprofen Indomethacin Irbesartan Losartan Phenytoin Rosuvastatin S-warfarin Siponimod Tamoxifen CYP2C19 Amitriptyline Cilostazol Citalopram Clomipramine Clopidogrel Diazepam Imipramine Lansoprazole Naproxen Omeprazole Pantoprazole Phenobarbital Phenytoin Propranolol CYP2D6 Amitriptyline Aripiprazole Atomoxetine Carvedilol Clomipramine Clozapine Codeine Dextromethorphan Donepezil Duloxetine Flecainide Fluoxetine Fluvoxamine Haloperidol Hydrocodone Imipramine Metoprolol Mirtazapine Nebivolol Nortriptyline Oxycodone Paroxetine Propafenone Propranolol Risperidone Tamoxifen Thioridazine Timolol Tramadol Trazodone Venlafaxine CYP3A4 Alprazolam Amiodarone Amlodipine Aprepitant Aripiprazole Atorvastatin Boceprevir Buprenorphine Buspirone Carbamazepine Cilostazol Citalopram Clarithromycin Cyclosporine Dapsone Darunavir Delavirdine Diazepam Diltiazem Donepezil Efavirenz Eplerenone Erlotinib Erythromycin Ethinyl estradiol Felodipine Fentanyl Finasteride Fosamprenavir Gefitinib Imatinib Irinotecan Itraconazole Ketoconazole Lapatinib Lidocaine Lovastatin Methadone Midazolam Mirtazapine Nateglinide Nevirapine Nifedipine Quetiapine Quinidine Repaglinide Rifabutin Ritonavir Sertraline Sibutramine Sildenafil Simvastatin Siponimod Sirolimus Sorafenib Sunitinib Tacrolimus Telaprevir TCAs ( amitriptyline, clomipramine, imipramine) Tiagabine Trazodone Triazolam Vardenafil Verapamil Voriconazole Zaleplon Ziprasidone Zolpidem Zonisamide Nomenclature CYP 3 A 4 specific enzyme subfamily (> 70% identical in amino acid sequence) family (> 40% identical in amino acid sequence) GENE for mammalian cytochrome Figure 1. Nomenclature. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-85 Pharmacokinetics: A Refresher 2. Distribution of CYP isoenzymes in human liver 1A2 11% 1A2 13% Other 26% 2E1 7% 2E1 4% 2B6 3% 2A6 3% 3A4 36% 2A6 4% 2D6 2% 2D6 19% 2C 18% 2C19 8% 3A4 30% ContentContent 2C9 16% RoleininCYP-Mediated CYP-Mediated Drug Role Drug Elimination Elimination Figure 2. Distribution of CYP isoenzymes in human liver. 3. Distribution of CYP isoenzymes in human GI tract Other CYPs 30% CYP3A4 70% Figure 3. Distribution of CYP isoenzymes in human gastrointestinal tract. 4. Characteristics of CYP metabolism a. Inhibition is substrate-independent. b. Some substrates are metabolized by more than one CYP (e.g., tricyclic antidepressants [TCAs], selective serotonin reuptake inhibitors [SSRIs]). c. Enantiomers may be metabolized by different CYP isoenzymes (e.g., R- vs. S-warfarin). d. Differences in inhibition may exist in the same class of agents (e.g., fluoroquinolones, azole antifungals, macrolides, calcium channel blockers, histamine-2 blockers). e. Substrates can also be inhibitors (e.g., erythromycin, verapamil, diltiazem). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-86 Pharmacokinetics: A Refresher f. Most inducers and some inhibitors can affect more than one isozyme (e.g., cimetidine, ritonavir, fluoxetine, erythromycin). g. Inhibitors may affect different isozymes at different dosages (e.g., fluconazole inhibits CYP2C9 at dosages of 100 mg/day or greater and inhibits CYP3A4 at dosages of 400 mg/day or greater). 5. Drug interactions a. Induction – Adaptive increase in enzyme activity in response to another agent – Slow, regulatory process i. Induction is dose-dependent. ii. Onset – Usually begins after several days, with a maximal effect within 2 weeks (somewhat dependent on the potency and half-life of the inducer) iii. Offset – Usually longer to eliminate enzymes than to generate enzymes; enzyme activity returns to normal within 2–3 weeks (somewhat dependent on the half-life of the inducer) b. Inhibition – Direct action on an enzyme that renders the enzyme inactive i. Inhibition is dose-dependent. ii. Onset – Quicker than induction (inhibition begins as soon as the inhibiting agent is in the system), but dependent on the half-life of the inhibiting agent and the substrate (i.e., time to steady state for both agents) iii. Offset – Effect is gone as soon as the inhibiting agent is eliminated. C. P-Glycoprotein 1. P-glycoprotein is an efflux pump that pumps drugs into the bile; the clinical effect of P-glycoprotein drug interactions in the bile is unknown. 2. P-glycoprotein pumps drugs from renal tubules into the urine; it also potentially limits the degree of reabsorption. 3. Examples of drug interactions: quinidine/digoxin, cyclosporine/digoxin, and propafenone/digoxin Patient Case 5. W.T., a 62-year-old man who presents to the emergency department with chest pain, is given a diagnosis of a non-ST-segment elevation myocardial infarction. He goes to the catheterization laboratory, where two drug-eluting stents are placed. After stent placement, he is initiated on aspirin 81 mg daily and clopidogrel 75 mg daily. A CYP2C19 pharmacogenetic test shows that he is a poor metabolizer (CYP2C19*3/*3 genotype). The patient also receives losartan 25 mg daily, carvedilol 25 mg twice daily, amitriptyline 100 mg daily, acetaminophen 500 mg as needed, and atorvastatin 40 mg daily. Given his pharmacogenetic profile, which is most likely to occur in this patient? A. He will form a metabolite of clopidogrel that will block the action of aspirin, increasing the risk of a thrombotic event. B. He will not activate clopidogrel well, increasing the risk of a thrombotic event. C. He will not metabolize clopidogrel well, increasing the risk of a bleeding event. D. He will overproduce an active metabolite of clopidogrel, increasing the risk of a bleeding event. D. Pharmacogenetics 1. Population in general is divided into poor, intermediate, extensive, and ultrarapid metabolizers; therefore, metabolism is considered polymorphic. 2. Definition of polymorphism: Coexistence of more than one genetic variant (alleles), which are stable components in the population (more than 1% of population) 3. Clear antimode (separation between the two populations) results ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-87 Pharmacokinetics: A Refresher No. of Patients antimode PM EM URM Metabolic ratio of metabolite to unchanged drug ° (increasing metabolic capacity) Figure 4. Distribution of patients in a drug that follows polymorphic metabolism. EM = extensive metabolizer; PM = poor metabolizer; URM = ultrarapid metabolizer. 4. Phenotype: Expression of the trait; interaction of gene with environment a. Manifestation of the trait clinically b. Not necessarily constant 5. Genotype: Genetic makeup 6. Pharmacogenetics in clinical practice (Table 8) Table 8. Pharmacogenetics in Drug Metabolism, Drug Transport, Drug Target, and Adverse Drug Reactions Type Drug metabolism Enzyme/Target CYP2C9 Most Common Variant Alleles CYP2C9*2 (70%–90% activity) CYP2C9*3 (10%–30% activity) Drug metabolism CYP2C19 CYP2C19*2 (poor) CYP2C19*3 (poor) CYP2C19*17 (ultrarapid) CYP2C19*4 (null variant) Drug metabolism CYP2D6 CYP2D6*10 (poor) CYP2D6*17 (poor) CYP2D6*3, *4, and *5 (null) Drug metabolism UDPUGT1A1*6 glucuronosyltransferases UGT1A1*28 UGT2B7*2 UGT2B7*28 N-acetyltransferase NAT2*4 NAT2*5 NAT2*6 NAT2*7 Drug metabolism Drug Examples NSAIDs Phenytoin Siponimod Warfarin Clopidogrel Diazepam Omeprazole SSRIs Tricyclic antidepressants Voriconazole Antiarrhythmics Antipsychotics Beta blockers Codeine, hydrocodone, oxycodone Dextromethorphan SSRIs Tamoxifen Tramadol Tricyclic antidepressants Atazanavir Irinotecan Mycophenolate NSAIDs Hydralazine Isoniazid Sulfasalazine ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-88 Pharmacokinetics: A Refresher Table 8. Pharmacogenetics in Drug Metabolism, Drug Transport, Drug Target, and Adverse Drug Reactions (Cont’d) Type Drug transport Enzyme/Target SLCO1B1 Drug target VKOR Adverse drug reactions HLA-B Most Common Variant Alleles SLCO1B1*1A,*1B SLCO1B1*5, *15, *17 VKORC1*2 (increases) VKORC1*3 (decreases) HLA-B*5701 HLA-B*5801 HLA-B*1502 Drug Examples Simvastatin Warfarin Abacavir Allopurinol Carbamazepine, phenytoin NSAID = nonsteroidal anti-inflammatory drug; SSRI = selective serotonin reuptake inhibitor. 6. Clinical Pharmacogenetics Implementation Consortium (CPIC) a. Designed to facilitate translation of pharmacogenetics information from research to clinical practice b. Developing guidelines for use of pharmacogenetic test results in drug dosing c. Focused on specific drug-gene pairs (Table 9) Table 9. CPIC Clinical Recommendations for Drug-Gene Pairs Drug Gene Recommendation Abacavir HLA-B Avoid using because of increased incidence of hypersensitivity reactions in patients with the HLA-B*57:01 allele Allopurinol HLA-B Avoid using because of increased incidence of severe cutaneous adverse reactions in patients with the HLA-B*58:01 allele Aminoglycosides: Amikacin, Gentamicin, Tobramycin MT-RNR1 Avoid using in patients with certain variants of MT-RNR1 because of increased risk of aminoglycoside-induced hearing loss. Atazanavir UGT1A1 For patients who carry 2 decreased function UGT1A1 alleles, increased risk of jaundice and subsequent nonadherence Consider alternative agents Slower dose titration in intermediate and poor metabolizers. In addition, obtain plasma concentrations 2–4 hr after dosing instead of 1–2 hr Atomoxetine CYP2D6 Capecitabine/5-fluorouracil/ tegafur DPYD Avoid using in poor metabolizers. Decrease dose by 50% in intermediate metabolizers. Carbamazepine/oxcarbazepine HLA-A HLA-B Avoid using because of increased incidence of severe cutaneous adverse reactions in patients with the HLA-A*31:01 or HLA-B*15:02 allele Clopidogrel CYP2C19 Normal dosing for ultrarapid, rapid, and normal metabolizers; alternative antiplatelet therapy in intermediate or poor metabolizers Codeine Tramadol Efavirenz CYP2D6 Avoid using codeine or tramadol because of potential toxicity or lack of efficacy in ultrarapid and poor metabolizers In intermediate and poor metabolizers, consider initiating lower doses of efavirenz (200–400 mg/day) Irinotecan UGT1A1 Reduce the starting dose of irinotecan for UGT1A1*28 homozygous patients receiving more than 250 mg/m 2 Ivacaftor CFTR Recommended only for patients with cystic fibrosis who have certain variants as noted in the package insert CYP2B6 ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-89 AL GRAWANY Pharmacokinetics: A Refresher Table 9. CPIC Clinical Recommendations for Drug-Gene Pairs (Cont’d) Drug Gene Recommendation NSAIDs: Celecoxib, Ibuprofen, Meloxicam CYP2C9 In intermediate metabolizers, start with lowest recommended starting dose (celecoxib/ibuprofen) or 50% of lowest recommended starting dose (meloxicam) and titrate to clinical effect. In poor metabolizers, start with 25%–50% of the lowest recommended starting dose and titrate to clinical effect or 25%–50% of the maximum recommended dose (celecoxib/ibuprofen). Do not use meloxicam in poor metabolizers Ondansetron CYP2D6 Phenytoin/Fosphenytoin CYP2C9 HLA-B Select an alternative drug that is not predominantly metabolized by CYP2D6 (i.e., granisetron) in CYP2D6 ultra-rapid metabolizers Reduce initial dosage by 25% in CYP2C9 intermediate metabolizers with activity score of 1.0 and by 50% in poor metabolizers Severe cutaneous adverse reactions associated with carriers of the HLA-B*15:02 allele; use an alternative anticonvulsant PPIs: Lansoprazole Omeprazole Pantoprazole Rasburicase Siponimod CYP2C19 SSRIs: Citalopram: 2C19 Escitalopram: 2C19 Sertraline: 2C19 Fluvoxamine: 2D6 Paroxetine: 2D6 Statins: Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin CYP2D6, CYP2C19 G6PD CYP2C9 For CYP2D6 poor metabolizers, consider a 25%–50% reduction of recommended starting dosage SLCO1B1 ABCG2 CYP2C9 Tacrolimus CYP3A5 Tamoxifen CYP2D6 Thiopurines (azathioprine, 6-mercaptopurine, thioguanine) Tricyclic antidepressants TMPT NUDT15 CYP2D6, CYP2C19 Voriconazole Warfarin Increase starting dose by 100% in ultrarapid metabolizers, consider increasing dose by 50%–100% in rapid and normal metabolizers, use standard dose but consider decreasing dose by 50% if used longer than 12 weeks in intermediate and poor metabolizers. Contraindicated in those with G6PD deficiency Maximum 1 mg dose in poor/intermediate metabolizers (*1/*3, *2/*3) and 2 mg in normal/intermediate metabolizers (*1/*1, *1/*2, *2/*2) Alternative drug not predominantly metabolized by CYP2C19 for CYP2C19 ultrarapid metabolizers, and for CYP2C19 poor metabolizers, consider a 50% reduction of recommended starting dosage CYP2C19 VKORC1/ CYP2C9 Limit doses of all statins or avoid certain statins in patients with decreased or poor function of SLCO1B1. Limit dose of rosuvastatin to no more than 20 mg daily in patients with poor function of ABCG2. Limit dose of fluvastatin in patients who are CYP2C9 intermediate or poor metabolizers. Increase starting dosage by 1.5 to 2 times in CYP3A5 intermediate or extensive metabolizers (not to exceed 0.3 mg/kg/day) Use alternative hormonal therapy for CYP2D6 poor metabolizers (also consider alternative for CYP2D6 intermediate metabolizers) Dosing recommendations for each drug based on TMPT and NUDT15 genotypes (normal/high, intermediate, and low activity) Dosing recommendations for depression based on metabolizer status (ultrarapid, extensive, intermediate, poor) Limited recommendations when using for peripheral neuropathy Select an alternative agent that is not dependent on CYP2C19 metabolism, such as isavuconazole, liposomal amphotericin B, or posaconazole, in ultra-rapid and rapid CYP2C19 metabolizers Select an alternative agent that is not dependent on CYP2C19 metabolism in poor CYP2C19 metabolizers, or initiate at a lowerthan-normal dose and perform careful therapeutic drug monitoring Use available table or algorithms to initiate warfarin dosing based on VKORC1 and CYP2C9 genotypes ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-90 Pharmacokinetics: A Refresher V. NONLINEAR PHARMACOKINETICS Patient Case 6. C.M. is a 55-year-old man who is initiated on phenytoin after a craniotomy. His current steady-state phenytoin concentration is 6 mg/L at a dosage of 200 mg/day by mouth. If his affinity constant (Km) is calculated to be 5 mg/L, which is most likely to occur if the dosage is doubled (to 400 mg/day by mouth)? A. His concentration will double because phenytoin clearance is linear above the Km. B. His concentration will more than double because phenytoin clearance is nonlinear above the Km. C. His concentration will stay the same because phenytoin is an autoinducer, and clearance increases with time. D. H  is concentration will increase by only 50% because phenytoin absorption decreases significantly with dosages greater than 300 mg. A. Michaelis-Menten Pharmacokinetics V *S Km + S max velocity = –––––––– Vmax = capacity constant (amount/time) K m = affinity constant (amount/volume) S = substrate concentration (amount/volume) B. Nonlinear Elimination 1. Saturation or partial saturation of the elimination pathway Vmax * C rate of elimination (dose) = –––––––– Km + C Vmax = maximum rate of elimination (amount/time) K m = concentration where elimination is ½ Vmax (affinity constant) C = drug concentration 2. Note: Nonlinearity occurs when concentration is at or above K m. Example: Phenytoin Vmax normal = 7 mg/kg/day b. K m normal = 5.6 mg/L a. c. 50% variability between individuals VI. NONCOMPARTMENTAL PHARMACOKINETICS A. Why Noncompartmental Pharmacokinetics? 1. Identification of the “correct” model is often impossible. 2. A compartmental view of the body is unrealistic. 3. Linear regression is unnecessary; it is easier to automate analysis. 4. Requires fewer and less stringent assumptions 5. More general methods and equations 6. There is no need to match all data sets to the same compartmental model. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-91 Pharmacokinetics: A Refresher B. Definitions 1. Zero moment concentration versus time curve • Area under the curve (AUC) (Cn+l + Cn) 2 Clast k AUC = ∑ ––––––––– * (tn+l – tn)... + ––– 2. First moment concentration * time versus time curve • Area under the first moment curve (AUMC) (Cn+l * tn+l + Cn * tn) Clast * tlast Clast AUMC = ∑ ––––––––––––––––– * (tn+l – tn)... + –––––––– + –––– 2 k k2 3. Mean residence time (MRT) AUMC MRT = ––––––– AUC 4. Mean absorption time (MAT) MAT = MRTev − MRTiv C. Pharmacokinetic Parameter Estimation 1. Clearance dose Clearance = ––––– AUC 2. Vd at steady state dose * AUMC Vss = ––––––––––––– AUC2 3. Elimination rate constant 1 k = –––––– MRT 4. Absorption rate constant 1 ka = ––––– MAT 5. Bioavailability Div * AUCev F = –––––––––––– Dev * AUCiv VII. DATA COLLECTION AND ANALYSIS A. Timing of Collection 1. Ensure completion of absorption and distribution phases (especially digoxin [8–12 hours] and aminoglycosides [30 minutes after infusion]). 2.  Ensure completion of redistribution after dialysis (especially aminoglycosides [3–4 hours after hemodialysis]). B. Specimen Requirements 1. Whole blood: Use anticoagulated tube. Examples: cyclosporine, amiodarone 2. Plasma: Use anticoagulated tube and centrifuge; clotting proteins and some blood cells are maintained. 3. Serum: Use red top tube, allow to clot, and centrifuge. Examples: most analyzed drugs including aminoglycosides, vancomycin, phenytoin, and digoxin ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-92