Outline 8/2/2013. PK/PD PK/PD first-line drug กก PK/PD กก

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1 Pharmacokinetic and pharmacodynamic of anti- tuberculosis drugs Outline PK/PD PK/PD first-line drug กก PK/PD กก Concentration vs time in tissue and other body fluids Pharmacologic or toxicologic effect Dosage regimen Concentration vs time in serum Absorption Distribution Elimination Concentration vs time at site of infection Antimicrobial effect vs time Pharmacokinetics what the body does to the drug Pharmacodynamics what the drug does to the body Clin Infect Dis. 1998;26:1-12 HIV and HIV-tuberculosis patients who have diarrhea and cryptosporidial infection exhibit decreased bioavailability of antituberculosis drugs. Antimicrob Agent Chemother 2004;48: The concentration of INH in human serum declines due to metabolism by aryl-amine N- acetyltransferase-2 (NAT2) Antimicrob Agent Chemother 2005;49: Antimicrob Agent Chemother 2004;48:

2 The PK/PD parameter used to try to predict the outcome of therapy via pharmacological indices determined from in vitro model, animal models or clinical trials.. PK/PD modeling combines a PK model component that describes the time course of drug in plasma and a PD model component that relates the plasma concentration to the drug effect in order to describe the time course of the effect intensity resulting from the administration of a certain dosage regimen International Journal of Impotence Research , PK/PD Parameter T>MIC Peak/MIC 24-h AUC/MIC MIC provide useful information regarding the intrinsic activity of antimicrobial against pathogens MIC as good measure of antibacterial activity/ mechanism of resistance 1 It does not represent the concentration at which growth ceases and does not distinguish between static and cidalactivity. 2 Current opinion in critical care 2006;12: Journal of Antimicrobial Chemotherapy (2003) 52, Tuberculosis 2008;88(suppl 1):S65-S74 Definition: the cumulative percentage of time over a 24 h period that the drug concentration exceeds the MIC. T >MIC used to predict the efficacy of timedependent antibiotics. s that belong to these classes show no or little enhancement of the effect with an increase in antibiotic concentration. Low PAE T MIC of around 40-60% of the dosing interval are able to predict clinical and bacteriological success. IV beta-lactamantibiotic, the use of continuous intravenous drug infusions as the best route of administration to attain the PK/PD target as well as the maximum rates of microbiological eradication and clinical outcome. Journal of Antimicrobial Chemotherapy (2003) 52, Journal of Antimicrobial Chemotherapy (2003) 52,

3 C max /MIC = inhibitory quotient (IQ)= inhibitory rate (IR) The index is used to predict or describe the antibacterial effect of concentrationdependent antibiotic C max /MIC >8-10 is used to prevent antibiotic resistance Definition: the area under the concentration time curve over 24 h divided by the MIC. AUC/MIC (>125) is used to predict the efficacy of concentration-dependent antibiotics Journal of Antimicrobial Chemotherapy (2003) 52, Journal of Antimicrobial Chemotherapy (2003) 52, EurJ Clin Microbiol Infect Dis 2004;23: Concentration dependent: the major killing effect against an organism is produced by in crease the concentration of ATB (AUC/MIC 24hr ratios ) or (C/MIC >10) PAE refers to the persistent suppression of bacterial growth following exposure to an antimicrobial. Time-dependent drugs, the pharmacodynamic parameter can be simplified to the time that serum concentrations remain above the MIC (>50%) during the dosing interval (t>mic) Clin Microbiolo Infect 2001;7: Clinical Infectious Diseases 1998;26:1 12 3

4 RIF gave the longest PAE (67.8 h) The PAE induced by RIF was significantly longer than PAE produced by INH >PZA >EMB The combination of anti-tb yielded PAEs in descending magnitude by not significantly different. The PAE of anti-tb help in design of an optimal dosing schedule of intermittent therapy. Antimicrob. Agents Chemother 2001;45: Antimicrob. Agents Chemother 2001;45: EBA: the ability to decrease colony counts in quantitative sputum cultures early in the treatment of patients with pulmonary tuberculosis. absorption Distribution Metabolism Excretion isoniazid Ethambutol Rifampicin Rapidly and well absorbed (on empty stomach) C max 1-2 h Well absorbed (70-80%) C max 2-4 h Rapidabsorption; F90-95%(before enzyme induction); C max h( on empty stomach) Extensive, includeingcsf, ascites and pleural fluid Well distributed, but does not enter CSF; 40% protein bound Extensive distribution (body fluids discoloured); good CSF penetration in the presence of inflamed meninges;80% protein bound Acetylation (pharmacogenetic variability: autosomal dominant: slow and fast acetylator 15% metabolised to aldehyde and dicarboxylic metabolites Undergoes enterohepatic circulation; deacetalation; active metabolite; hepatic enzyme inducer T 1/2 inslow acetylators 2-4.5h, in rapid acetylators h:75-95% excreted in urine T 1/2 3-4h; 75% excreted unchanged in urine T 1/2 2-5h (falls after repeated dosages due to enzyme induction); 30% excreted in urine; 65% excreted in faeces absorption Distribution Metabolism Excretion Pyrazinamide Well absorbed; C max 2 h; goof F in combination form Streptomycin Rapid absorption after IM; C max <1 h CIP/OFX Cyclocerine Well absorbed; C max <2 h Rapid absorbed; C max 3-4h Widely distributed (including CSF); 5% protein bound Wide tissue distribution; poor CSF penetration; 34% protein bound Widely distributed Widely distributed; good CSF penetration Hydrolysed and hydroxylated to 5- hydroxy-pyrazinoic acid No identified metabolites CIP has several metabolites:ofx is not metabolised T 1/2 9.5h; metabolites excreted by renal glomerular filtration; 3% excreted unchaged T 1/2 2-4 h; 90% excreted unchanged in urine T 1/2 for CIP 3-6 h, OFX 5-7.5h, renal excreted T 1/2 10h; 70% excreted in urine with 72h Daily Dose and range (mg/kg body weight) Maximum (mg) Recommended 3 times per week Dose and range (mg/kg body weight) Daily maximum (mg) Isoniazid 5 (4 6) (8 12) 900 Rifampicin 10 (8 12) (8 12) 600 Pyrazinamide 25 (20 30) - 35 (30 40) - Ethambutol 15 (15 20) - 30 (25 35) - Streptomycin 15 (12 18) 15 (12 18) 1000 Clin Pharmacokinet 1999;37: World Health Organization

5 FDC dose recommended RifafourE-275 (INH 75, RIF 150, EMB 275, PZA 400) wt dose kg kg kg 4 >71 kg 5 Rifinah150 (INH 100, RIF 150) wt<50 kg 3 Rifinah300 (INH 150, RIF 300) wt>50 kg 2 High Speed of bacterial growth Low A Continuous growth D Dormant INH,EMB (RIF, SM) B PZA Acid inhibition C RIF Spurts of metabolism Mitchison DA. 1979;76: Method :225 outpatients with TB had blood samples collected 1, 2, 6 h after standard anti-tb treatment Botswana ministry of health daily dose guidelines for anti-tb Dose by body weight kg >50 kg Isoniazid Rifampicin Ethambutol Pyrazinamide Clin Infect Dis 2009;48: HIV uninfected (n=70) C max median µg/ml(range) HIVinfected with CD4 cell count 200 cells/µl (n=71) HIV infected with CD4 cell count <200 cells/µl (n=84) INH 4.1 ( ) 4.2 ( ) 4.3 ( ) 0.80 RIF 4.6 ( ) 5.7 ( ) 4.4 ( ) <0.04 EMB 2.2 ( ) 2.4 ( ) 2.1 ( ) 0.50 PZA 52.3( ) 49.9 ( ) 46.9 ( ) <0.04 Median RIF and PZA levels differed significantly by HIV status and CD4 cell count category. Low PZA C max was associated with poor treatment outcome. p Clin Infect Dis 2009;48: C 2h levels of antituberculosis drugs and doses administered to Tanzanian subjects as fixed- dose tablet combinations at 14 days Fourteen (88%) had C 2h rifampin levels and 11 (69%) had isoniazid levels below 90% of the lower limit of the expected range. Antimicrob. Agents Chemother. 2011;55:

6 INH microbial kill cease after 2-3 day of therapy. INH is thought to kill bacilli in log-phase growth The bactericidal action of INH is dose related, reaches a plateau at a dose of approximately 300 mg and can be detected at a dose as low as 180 mg. OD dose more effective than BID dose EBA which is the average rate of sputum bacillary decline during the first 2 days of therapy is the index term of INH microbial killing activity The cessation of microbial kill occurred between days 3 and 4 of isoniazid therapy, as occurs in patients. Dose of 150 mg/day were associated with maximal microbial killing. Antimicrob Agent Chemother 2007;51: CHEST 1979;76: JID 2007;195: Tuberculosis 2008;88:s75-s83 AUC/MIC correlated best with the bactericidal efficacy, followed by Cmax/MIC Dose (mg/kg) PK parameter Cmax (µg/ml) AUC 24 (mg-h/l) Rapid 5 5.4± ±6.1 Slow 5 7.1± ±1.5 MIC90 (µg/ml) PD parameter Cmax/MI C AUC/MIC Rapid Slow American patients Chinese patients Rapid acetylatorsare more common in Japanese, Eskimo, Lapland, Indian and black African. Slow acetylatorsare more common in the caucasianpopulation eg; America and Europe, approximately 40% EurJ Clin Microbiol Infect Dis 2004;23: Clin Pharmacokinet 1999;37: Antimicrob Agent Chemother 2007;51:

7 More bactericidal activity in slow acetylatorsgroup than fast acetylators group Antimicrob Agent Chemother 2007;51: Any dose reduction below 6 mg/kg body weight will tend to disadvantage a significant proportion of faster acetylators, but, conversely, SS acetylators require only a 3 mg/kg dose to achieve a satisfactory exposure to INH. Mechanism of action: inhibit bacterial DNA-dependent RNA polymerase RIF active against both extracellular and intracellular M. tuberculosis, even under slow replicative conditions Potent CYP3A inducer (rifampicin>rifapentin>rifabutin) RIF induced hepatitis particularly in patients with chronic liver disease, alcoholism, poor nutrition and elderly. Need Cmax/MIC >175 EurJ Clin Pharmacol2007;63:633-9 RIF exhibited an E max that resulted in a 6 log 10 CFU/mLreduction on day 1 to day7. RIF exhibited AUC dependent killing effect in vitro, with maximal killing seen on all day and with the potency increasing steadily over a 9 day exposure period. RIF rapidly penetrates mammalian cells and accumulates to 4 to 5 fold higher levels in the intracellular environment than in the extracellular environment. Tuberculosis 2008;88:s75-s83 Antimicrob Agent Chemother 2003;47:

8 In mouse model, RIF dose 10 mg/kg of body weight is low Pattern of activity of RIF is type I Goal of therapy is maximize concentration PK/PD parameter AUC/MIC showed the best correlation with the best bactericidal efficacy of RIF C max /MIC Antimicrob Agent Chemother 2003;47: Antimicrob Agent Chemother 2003;47: PK of RIF in varies dose Patient characteristic NS SIG AUC in the study was significantly greater than that after an RIF dose of 600 mg This study find the near-linear increase of the 2 day EBA of RIF with a dose double that used in standard regimen Antimicrob Agent Chemother 2007;51: Standard RIF dose 10 mg/kg Antimicrob Agent Chemother 2007;51: mg/kg 13 mg/kg Grade 1 or 2 hepatotoxicitywas more common in the higher dose group (P=0.054) No serious hepatotoxicity ADR occurred in the first weeks No flu-like syndrome AUC 0-24 were increased by 65% (p<0.001) C max were 15.6 mg/l vs10.5 mg/l (49% increase; P < 0.001). Antimicrob Agent Chemother 2006;50:822-3 Antimicrob Agent Chemother 2007;51:

9 ACs plasma ELF ACs plasma ELF RIF 600mg RIF 1200mg Standard dose (600 mg) and higher dose (1200 mg) is sufficient to prevent the development of resistant Intracellular concentrations appeared to be more effective for the prevention of resistance at low MIC (<0.01 mg/lit), but the level of target attainment decreased to less than 50% when MIC was 0.05 mg/lit The decline in microbial density were similar in all three dosing schedule 0.05 Antimicrob Agent Chemother 2007;51: Antimicrob Agent Chemother 2009;53: plasma RIF 600mg ELF plasma RIF 1200mg ELF AUC 0-24 /MIC 217 The killing effect of RIF against M. tuberculosis correlated well with AUC 0-24 /MIC ELF concentrations = extracellular concentration RIF 1200 mg dose had a favorable effect on the target attainment results. Antimicrob Agent Chemother 2009;53: Clinical Infectious Diseases 2006; 43: Common AE; N/V Hepatitis occurring in 2.5% Flu-like syndrome (fever, myalgia, chills, arthralgia) Thrombocytopenia Acute renal failure PZA has been shown to inhibit various functions at acid ph in M. tuberculosis PZA works in the cavities under acidic conditions. Microbial killing of PZA may occur via the reduction of the intracellular ph, the disruption of membrane transport, inhibition of fatty acid synthase type I. 9

10 Dose (mg/kg) PK parameter Cmax (µg/ml) AUC 24 (mg-h/l) PZA ± ±101 MIC90 (µg/ml) PD parameter Cmax/MIC AUC/MIC PZA ±0.6 52±10 ph 5 EurJ Clin Microbiol Infect Dis 2004;23: PZA requires acidic condition to inhibit M. tuberculosis Antimicrob. Agents Chemother 2009;53: PZA is concentration dependent Resistance suppression was associated with the percentage of time that the concentration persisted above the MIC (r2 = 0.73 to 0.91). Antimicrob Agent Chemother 2009;53: control Once a week No EBA 30 mg/kg 15mg/kg PZA had no EBA in the first 4 day. PZA dose 15 mg/kg and 30 mg/kg failed to decrease M. tuberculosis density between weeks 2 and 3. The schedule of pyrazinamide administration once a week had the worst outcome, while daily therapy had the best result, consistent with an effect linked to T MIC. Antimicrob Agent Chemother 2009;53: Antimicrob Agent Chemother 2009;53:

11 The slopes of C max /dosage of the fitted lines are 1.32 (SE 0.099) for pediatric patients, 1.36 (SE 0.051) for adult volunteers and 1.35 (SE 0.037) Children can receive the same mg/kg body weight PZA dosage as adults. Tuberculosis 2012;92:1-8 The C max of pyrazinamide was significantly lower in younger children (<5 years) than in older children. The C max of pyrazinamide was also lower for HIVinfected children and children with severe malnutrition, but non statistical significance. Standard weight banding reveals that more than 50% of subjects in the weight range of 45 to 55 kg remain below the proposed target exposure to PZA Antimicrobial Agents and Chemotherapy, July 2006;50; Antimicrob Agents Chemother 2012;56: Meta-analysis from 29 studies suggested that high-dose pyrazinamidedid not significantly increase hepatotoxicity. The frequencies of hepatotoxicity were (CI, to 0.067) for 30 mg/kg (CI, to 0.094) at 40 mg/kg, (CI, to 0.193) at 60 mg/kg Inhibit topoisomeraseii (DNA gyrase) of M. Tuberculosis. Exert the intracellular bactericidal activity. The fluoroquinoloneshave shown bactericidal activity close to, or equal to INH AUC/MIC, C/MIC were correlated well with the antimicrobial activity of fluoroquinolone Antimicrobial Agents and Chemotherapy, July 2010;54; Tuberculosis :S

12 MXF produces the greatest AUC/MIC in standard human dose The low AUC/MIC ratio of (AUC/MIC in S. pneumoniae= ) is sufficient to achieve clinical and microbiological success in TB In patient with active TB, MXF was shown to be similar to RIF in term of bactericidal activity (EBA) Journal of Antimicrobial Chemotherapy (2004) 54, EurJ Clin Microbiol Infect Dis 2004;23: MFX SPX OFX CIP MFX exhibited the highest bactericidal activity on all day. MFX>OFX>SPX Using the EBA method, isoniazid was significantly more active than rifampin (p< 0.01) but not moxifloxacin. Am J Respir Crit Care Med 2003;168: Ethambutol MFX INH Substitution of moxifloxacinfor isoniazid resulted in a small but statistically nonsignificant increase in Week-8 culture negativity Microbial kill in the Hollow-fiber study was linked to AUC 0-24 /MIC. EMB had a maximal EBA 0.22 log 10 CFU/mL/day and after 2 days the maximal kill rates fell to log 10 CFU/mL/day The EBA 0-2 of EMB dose 15 mg/kg was 0.05 that lower than EMB dose 25 mg/kg was also give EBA Am J Respir Crit Care Med 2009;180: Tuberculosis 2008;88:S

13 High dose of EMB (50 mg/kg) associated with ocular toxic. Intermittent dosing lower toxic than daily dose. Toxicity is driven by AUC but not by C max. Obese patients is increasing risk to ocular toxic from EMB. The dose of EMB should be based on ideal body weight and not on total body weight. 1. High dose of anti-tb Rimstar :INH 75, RIF 150, EMB 275, PZA 400 Antimicrob Agent Chemother 2010;54: Weight, kg Rifater (R 120+H 50+ Z 300) Weight, kg Rimcure (R 150+H 75+ Z 400) Rimstar (R 150+H 75+ Z 400+ E 275) < > >64 6 Continuation Phase:4 months Weight, Rifinah Rimactazid kg (R 300+H 150) (R 300+H 150) Tisobrif (R 600+H 300) Wt Rimstar INH RIF EMB PZA < > Pt / /450 New dose / / / / / /600 6MKD 15 MKD 35 MKD