Pharmacokinetics (PK) and Pharmacodynamics (PD) in the Treatment of Tuberculosis Shaun E. Gleason, PharmD, MGS Associate Professor, Department of Clinical Pharmacy Director, Distance Degrees and Programs University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences Disclosure: Past employee & current stockholder of Johnson & Johnson Family of Companies April 2018
Same as it ever was. Yeah, the twister comes Here comes the twister Same as it ever was. - Once in a Lifetime, Talking Heads 1 Egelund EF, Alsultan A and Peloquin CA. Optimizing the clinical pharmacology of tuberculosis medications. Clin Pharm Ther 2015; 2015;98(4):387-393. 2
Learning Objectives At the end of this presentation, the learner will be able to: Describe the basic concepts of PK/PD, specifically: the fundamentals of PK the difference between PK and PD Describe the use of PK / PD principles in TB therapy, in particular, related to these in the use of: INH Rifamycins Aminoglycosides Discuss the use of Clinical PK / Therapeutic Drug Monitoring in TB in relation to: Optimizing efficacy Minimizing toxicity Patients needing it most 3
Intro to PK and PD Pharmacokinetics (PK): ADME: Study of the time course of Absorption, Distribution, Metabolism & Excretion. Clinical Pharmacokinetics The application of PK principles to the safe and effective therapeutic management of drugs in an individual patient aka Therapeutic Drug Monitoring (TDM) Pharmacodynamics (PD) Relationship between drug concentration at the site of action and the resulting effect DiPiro JT, Spruill WJ, Wade WE et al. Concepts in Clinical Pharmacokinetics, 5 th ed. Bethesda, MD : American Society of Health-System Pharmacists; 2010. p1-17. 4
KINETICS Pharmaco- Pharmaco- DYNAMICS Prescribed Dosing Regimen Drug at Site of Action Dosing & med errors Absorption Tissue & body fluid mass and volume Drug interactions Elimination Drug metabolism Adherence Genetic factors Drug interactions Tolerance Drug receptor status Effect of drug COMBOS Drug Effects DiPiro JT, Spruill WJ, Wade WE et al. Concepts in Clinical Pharmacokinetics, 5 th ed. Bethesda, MD : American Society of Health-System Pharmacists; 2010. p1-17.. 5
Pharmacokinetics 101 Assume plasma/serum concs = concs at site Bioavailability / Absorption Drug properties Pt factors Drug / food interactions Vol of Dist (Vd): dosing proportional to Vd Drug properties Pt factors DiPiro JT, Spruill WJ, Wade WE et al. Concepts in Clinical Pharmacokinetics, 5 th ed. Bethesda, MD : American Society of Health-System Pharmacists; 2010. p1-27. 6
Pharmacokinetics 101 Clearance (volume / time): measure of removal of drug from plasma Blood flow C in Organs of Elim n (Kidneys, Liver) Elimination C out Blood flow DiPiro JT, Spruill WJ, Wade WE et al. Concepts in Clinical Pharmacokinetics, 5 th ed. Bethesda, MD : American Society of Health-System Pharmacists; 2010. p19-27. 7
Pharmacokinetics 101 Half-life (T 1/2 ): Time for concs to decrease by 50% T 1/2 is independent of dose and concentration Regardless of conc, drug gone after 5-7 T 1/2 s A proportionality constant, dependent on Cl & Vd T 1/2 = 0.693 x Vd Clearance / Elimination: related to volume and T 1/2 of drug T 1/2 = 0.693/ K e K e = Cl / Vd Cl = K e x Vd K e = ln C 1 /C 2 / T DiPiro JT, Spruill WJ, Wade WE et al. Concepts in Clinical Pharmacokinetics, 5 th ed. Bethesda, MD : 8 American Society of Health-System Pharmacists; 2010; p29-44. Cl
PK Case AB PK Parameter AB is a 42 yo WM being treated for TB with SM 1000mg (~13 mg/kg) IV QM-F. Other meds: RIF/EMB/PZA AB has a h/o CHF, ESLD, and DM. Wt = 75 kg, Ht = 65 in. Labs: BUN = 15, SCr = 1.1 SM MIC = 8 mcg/ml Serum SM concs reveal: Calculated Cmax = 22 mcg/ml (nl=35-45 mcg/ml) Serum T 1/2 = 5.2 hrs (nl SM T 1/2 = 2-3 hrs) 9
Pt Case AB Question What is the most likely cause of AB s serum SM concentrations and PK parameters being not quite normal? a. Renal dysfunction b. Large volume of distribution c. Reduced absorption of the streptomycin d. Drug interaction affecting metabolism of SM 10
Use of PK / PD Principles in TB Therapy 11
PK/ PD Response Parameters Time > MIC More frequent dosing to maintain time above the MIC INH, Ethionamide AUC > MIC Cmax / MIC Concentration-dependent Best given as large (usually daily) doses Aim for ratio of at least 10-12 AMG s, FQ s, Rifamycins 12
PD: Response Parameters Conc 10 8 6 4 2 0 Cmax AUC > MIC MIC Cmax = 9 mcg/ml MIC = 3 mcg/ml Cmax/MIC = 3 T > MIC = 8h AUC (mcg * h/ml) 13
Ethionamide 2.5 2.0 1.5 1.0 0.5 0 Cmax MIC T > MIC = ~ 4h 14
INH Concs. by Acetylator status Conc. (mg/l) MIC SLOW = t ½ 3.35 hr, AUC 54.9 mcg*hr/ml Int.= t½ 1.56 hr, AUC 35.7 mcg*hr/ml FAST = t ½ 1 hr, AUC 25.0 mcg*hr/ml Time / Hours Parkin DP, Vandenplas S, Botha FJH, et al. Trimodality of Isoniazid: phenotype and genotype in patients with tuberculosis. Am J Respir Crit Care Med. 1997;155 (5):1717-22. 15
KINETICS Pharmaco- Pharmaco- DYNAMICS Prescribed Dosing Regimen Dosing & med errors Absorption Tissue & body fluid mass and volume Drug interactions Elimination Drug metabolism Adherence Drug at Site of Action Genetic factors Drug interactions Tolerance Pt factors Drug receptor status Effect of drug COMBOS Drug Effects DiPiro JT, Spruill WJ, Wade WE et al. Concepts in Clinical Pharmacokinetics, 5 th ed. Bethesda, MD : American Society of Health-System Pharmacists; 2010. p1-17. 16
PD: Impact of PK Mismatch PK Mismatch Short T 1/2 drug + long T ½ drug Resistance or Failure Reports in TB Strong relationship between low INH and therapeutic failure/relapse in QW INH/RPT 1 No effect of mismatch 2 : INH and rifampin Important in HIV co-infection 3, 4 1. Weiner M, Burman W, Vernon A, et al. Am J Respir Crit Care Med. 2003; 167: 1341-1347 2. Srivastava S et al. Antimicrob. Agents Chemother. 2011; 55: 5085-5089.. 3. Peloquin CA. Antimicrob. Agents Chemother. 2012; 56(3): 1666. 4. Egelund EF and Peloquin CA. Clin Infect Dis. 2012; 55: 178-179. 17
PK Mismatch PD Response: Low INH with Rifampin & Rifapentine PK Param INH Med AUC BIW I/Rif FAILURE / Relapse (n=16) Cure (n=33) PValue Weiner M et al. Am J Respir Crit Care Med. 2003; 167: 1341-1347.. QW I/Rpt FAILURE/ relapse (n=22) Cure (n=49) P Value 43.3 48.4 0.65 36.0 55.9 0.0005 Med Cmax 11.9 10.2 0.9 11.1 11.9 0.08 Med T1/2 2.1 2.3 0.42 1.4 2.4 0.02 Rifamycin Med AUC 46.1 50.5 0.23 211 196 0.47 Med Cmax 8.3 7.7 0.96 12.3 12.2 0.31 Med T1/2 2.2 3.4 0.11 14.6 16.8 0.04
Reduced Concentrations in HIV+ Rifampin HIV+ Hlthy vol Ethambutol HIV+ Hlthy vol Perlman DC et al for the ACTG 309 Team. The clinical pharmacokinetics of rifampin and ethambutol in HIV-infected persons with TB. Clin Infect Dis 2005; 41:1638-47. 19
EFFECT: RFB & INH AUC in HIV+ ARR Failures / Relapse N=5; Acquired rifamycin resistance (ARR) N=90; no ARR failure or relapse Weiner M et al. Association between acquired rifamycin resistance and the pharmacokinetics of 20 rifabutin and isoniazid among patients with HIV and tuberculosis.clin Infect Dis 2005; 40:1481-91.
ID (TB): Usual PK/PD Response Parameters Time > MIC More frequent dosing to maintain time above the MIC INH, Ethionamide AUC > MIC Cmax / MIC Concentration-dependent Best given as large (daily, intermittent) doses Aim for Cmax to MIC ratio of at least 10-12 (AMG s) AMG s, FQ s, Rifamycins 21
PD: Response Parameters 10 8 6 4 2 0 Cmax AUC > MIC MIC Cmax = 9 mcg/ml MIC = 3 mcg/ml Cmax/MIC = 3 T > MIC = 8h AUC (mcg * h/ml) 22
Streptomycin 70 60 50 40 30 20 10 0 mcg/ml Cmax MIC Cmax = 64 mcg/ml MIC = 8 mcg/ml Cmax/ MIC = 8 23
Rifampin 600 mg in Humans Cumulative % Culture Negative Month 1 2 3 H 300 R 600 Z 2 S 2 QD 38 77 97 H 300 R 600 Z 2 E 2 QD 35 77 99 Other doses: S750mg, Z 35mgkg, E 25mg/kg, R 450 mg if <50kg British Thoracic Association. A controlled trial of six months of chemotherapy in pulmonary tuberculosis. Br J Dis Chest 1981;75:141-153. 24
Rifampin 1200mg in Humans Cumulative % Culture Negative Month 1 2 3 H 900 R 1200 S 2 QD 72 94 98 H 900 R 1200 S 2 QOD* 70 93 100 Other doses: S 1000 mg QD* both regimens Kreis B, Pretet S. Two three-month treatment regimens for pulmonary tuberculosis. Bull Int Union Tuber 1976; 51:71-75. 25
Rifampin 600mg vs 1200mg Cumulative % Culture Negative Month 1 2 3 H 300 R 600 Z 2 S 2 QD 38 77 97 H 900 R 1200 S 2 QD 72 94 98 Other doses: S 750mg in first, 1000 mg QD in second Note: RIF dose response also seen with INH 300mg + RIF 450mg, 600mg, or 750mg QD (Long et al) Br J Dis Chest 1981; 75: 141-153. Kreis B et al. Bull Int Union Tuber 1976; 51: 71-75. Long MW, Snider DE, Farer LS. Am Rev Resp Dis. 1979; 119: 879-894. 26
Rifampin 1200mg Flu-like syndrome: NOT reported by Kreis et al More related to intermittent therapy May be best to optimize current regimens Kreis B et al. Bull Int Union Tuber 1976; 51:71-75. Egelund EF, Alsultan A and Peloquin CA. Optimizing the clinical pharmacology of tuberculosis medications. Clin Pharm Ther. 2015; 2015;98(4):387-393. Peloquin C. What is the right dose of rifampin? Int J Tuberc Lung Dis 2003; 7: 3-5. 27
Pt Case: AB Dose Optimization Recall that AB had an SM Cmax of 22 mcg/ml and an SM MIC of 8 mcg/ml. AB also had an extended serum T1/2 of 5.2 hrs. We are concerned about the effectiveness of this SM dose because of which dosing principle? a) The Time > MIC is not optimal b) The Cmax / MIC is not optimal c) The AUC > MIC is not optimal 28
Use of Therapeutic Drug Monitoring (TDM) in TB 29
Therapeutic Drug Monitoring (TDM)* GOAL: Optimization of therapy for individual pt: Maximize efficacy and/or Minimize toxicity Use with other clinical data Most valuable when *aka Clinical Pharmacokinetics Wide intersubject variation Therapeutic concs toxic concs Serum concs surrogate for concs at site of action DiPiro JT, Spruill WJ, Wade WE et al. Concepts in Clinical Pharmacokinetics, 5 th ed. Bethesda, MD : American Society of Health-System Pharmacists; 2010. p1-17. 30
TDM: What it s really about NOT necessarily normal ranges Rather, individualized goals for each pt. Goals should consider: Efficacy needs Toxicity acceptance Once drug is chosen: Determine desired conc. Try to achieve! Therapeutic concentrations vary by patient Jelliffe R. Goal-oriented, model-based regimens: setting individualized goals for each patient. Ther Drug Mon 2000; 22(3): 325-329. 31
100 Response * Probability ( % ) 50 Tx Range Potential ex: Cycloserine 15 25 35 45 Drug Concentration ( mcg / ml ) Toxicity Adapted from: Evans W in General Principles of Pharmacokinetic Michael E Burton, Leslie M Shaw, Jerome J Schentag, William E Evans. Applied Pharmacokinetics and Pharmacodynamics: Principles of Therapeutic Drug Monitoring. 4 th Edition 2006 32
TDM with TB Drugs May be more important than adherence(??) 1 Meta-analysis: PK variability to single drug associated with failure & acquired resistance Need at least 60% non-adherence to impact outcomes Useful for 2-4 Slow to respond to treatment Drug-resistant TB Risk of drug-drug interactions Concurrent disease (HIV, DM, Hep/renal dysfunction) 1. Pasipanodya JG et al. Clin Infect. Dis. 2012; 55: 169-77. 2. Peloquin CA. Use of Therapeutic Drug Monitoring in Tuberculosis Patients. Chest 2004; 126:1722-24. 3. Peloquin CA. Therapeutic Drug Monitoring in the Treatment of Tuberculosis. Drugs 2002; 62: 2169 2183. 4. Srivastava S et al; Therapeutic drug management: is it the future of multidrug-resistant tuberculosis treatment? Eur Resp J. 2013; 42: 1449-53. 33
PD: Drug tolerance Aminoglycoside Toxicity AK, SM, KM Regimens in TB and MAC: 12-15 mg/kg IV 5x/wk Cmax = 35-45 mcg/ml 22-25 mg/kg IV TIW Cmax = 65-80 mcg/ml Dose or serum concentrations did not predict: Hearing loss Vestibular toxicity Nephrotoxicity Conclusions Older pts minimize duration Larger pts ok to go >1000mg Peloquin CA, Berning SE, Nitta AT, et al. Aminoglycoside toxicity: daily versus thrice-weekly dosing for treatment of mycobacterial diseases. Clinical Infectious Diseases. 2004; 38:1538-1544. 34
Drug TDM: How to guide 1-2 hr postdose 6 hr postdose INH X X Rifampin X X Ethambutol X X 10 hr post-dose Pyrazinamide X X AK, SM, CM, KM* (*or 30 min /p infusion) X X X (ideally) Levo & Moxi X X Cycloserine X X PAS X X Ethionamide X X Two or more time-points ideal (better PK info) If can only do one, check the Cmax ( peak ; first one) Consult an expert Don t be afraid of the info! Dose max is not necessarily the max in your patient 35
Recall: Back to AB: AB is a 42 yo WM being treated for TB with: SM 1000mg (~13 mg/kg) IV QM-F, RIF 600 mg po QD, EMB 800 mg po QD, PZA 1000 mg po QD. AB has a h/o CHF and DM. 36
AB - Regimen Questions: Which other med(s) might we be most concerned about not being optimized in AB (and why)? a) Rifampin b) Rifampin and PZA c) Rifampin and Ethambutol 37
AB - Regimen Questions (cont d): Rifampin serum concs. reveal (nl = 8-24 mcg/ml): 2 hr: 6 mcg/ml 6 hr: 3 mcg/ml Without doing PK calculations, what might be a better new RIF dose (and why)? a) RIF 600 mg IV QD b) RIF 600 mg PO BID c) RIF 900 mg PO QD 38
Conclusions Overview of PK/PD PK time course ADME; PD - effect at site Therapeutic Drug Monitoring (TDM) PK / PD in TB INH time-dependent RIF, AMGs concentration dependent PK mismatch important, especially with INH and long half-life rifamycins (RFB and RPT) Use of TDM in TB Important in TB tx Offers individualized tx Efficacy / Toxicity Drug Interactions / Concurrent clinical problems 39
With an understanding of PK/PD and TDM, let s aim to make TB treatment NOT the same as it ever was. Egelund EF, Alsultan A and Peloquin CA. Optimizing the clinical pharmacology of tuberculosis medications. Clin Pharm Ther. 2015; 2015;98(4):387-393. 40
Questions? 41
References British Thoracic Association. A controlled trial of six months of chemotherapy in pulmonary tuberculosis. Br J Dis Chest 1981;75:141-153. DiPiro JT, Spruill WJ, Wade WE et al. Concepts in Clinical Pharmacokinetics, 5 th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2010. p1-44 Egelund EF and Peloquin CA. Pharmacokinetic variability and tuberculosis treatment outcomes, including acquired drug resistance. Clin Infect Dis. 2012; 55: 178-179. Egelund EF, Alsultan A and Peloquin CA. Optimizing the clinical pharmacology of tuberculosis medications. Clin Pharm Ther. 2015; 2015;98(4):387-393. Jelliffe R. Goal-oriented, model-based regimens: setting individualized goals for each patient. Ther Drug Mon 2000; 22(3): 325-329 Kreis B, Pretet S. Two three-month treatment regimens for pulmonary tuberculosis. Bull Int Union Tuber 1976; 51:71-75. Long MW, Snider DE, Farer LS. US publich health service cooperative trial of three rifampinisoniazid regimens in treatment of pulmonary tuberculosis. Am Rev Resp Dis. 1979; 119: 879-89. Li J et al. Use of Therapeutic Drug Monitoring in Tuberculosis Patients. Chest 2004; 126:1770-76. McCormack JP, Jewesson PJ. A critical re-evaluation of the therapeutic range of aminoglycosides. Clinical Infectious Diseases. 1992; 14: 320 339. Parkin DP, Vandenplas S, Botha FJH, et al. Trimodality of Isoniazid: phenotype and genotype in patients with tuberculosis.. Am J Respir Crit Care Med. 1997;155 (5):1717-22. Pasipanodya JG et al. Meta-analysis of clinical studies supports the pharmacokinetic variability hypothesis for acquired drug resistance and failure of antituberculosis therapy. Clin Infec. Dis. 42 2012; 55: 169-77.
References - continued Peloquin CA. Pharmacokinetic mismatch of tuberculosis drugs. Antimicrob. Agents Chemother. 2012; 56(3): 1666. Peloquin C. What is the right dose of rifampin? Int J Tuberc Lung Dis 2003; 7: 3-5. Peloquin CA. Use of Therapeutic Drug Monitoring in Tuberculosis Patients Chest 2004; 126:1722-24 Peloquin CA. Therapeutic Drug Monitoring in the Treatment of Tuberculosis. Drugs 2002; 62: 2169 2183. Peloquin CA, Berning SE, Nitta AT, et al. Aminoglycoside toxicity: daily versus thrice-weekly dosing for treatment of mycobacterial diseases. Clinical Infectious Diseases. 2004; 38:1538-1544. Perlman DC et al for the ACTG 309 Team. The clinical pharmacokinetics of rifampin and ethambutol in HIV-infected persons with TB. Clin Infect Dis 2005; 41:1638-47. Srivastava S et al. Pharmacokinetic mismatch does not lead to emergence of isoniazid- or rifampin-resistant Mycobacterium tuberculosis resistance but to better antimicrobbial effect: a new paradigm for antituberculosis drug scheduling. Antimicrob. Agents Chemother. 2011; 55: 5085-5089. Weiner M, Burman W, Vernon A, Benator D, Peloquin CA, Khan A, Weis S, King B, Shah N, Hodge T and the Tuberculosis Trials Consortium. Am J Respir Crit Care Med. 2003; 167: 1341-1347. Weiner M et al. Association between acquired rifamycin resistance and the pharmacokinetics of rifabutin and isoniazid among patients with HIV and tuberculosis.clin Infect Dis 2005; 40:1481-91 Weiner M, Burman W, Vernon A, et al. Low Isoniazid Concentration Associated with Outcome of Tuberculosis Treatment with Once-Weekly Isoniazid and Rifapentine. Am J Respir Crit Care 43 Med. 2003; 167: 1341-1347.