Multiple+Dosing+II

Multiple+Dosing+II - Multiple Dosing 1 Frequency of...

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Unformatted text preview: Multiple Dosing 1 Frequency of Administration 600 Half life = 1 day 160 mg - twice a day 160 mg - once a day 160 mg - every other day 320 mg/day 160 mg/day 80 mg/day 500 Amount in Body 400 300 200 100 0 0 2 4 6 8 10 12 14 Time in halflives 2 Changing Frequency and Dose 600 Half life = 1 day 80 mg - twice a day 160 mg - once a day 320 mg - every other day 160 mg/day 160 mg/day 160 mg/day 500 Amount in Body 400 300 200 100 0 0 2 4 6 8 10 12 14 Time in halflives 3 Average Amount/Concentration • Average In = Average Out (at S.S.) – No assumptions in this • Average In? – F*Dose/tau • Average Out? – dA/dt = -k A (k is elimination rate constant) – Average out = -k * Ass,avg • No assumption (but average is lnweighted) 4 Solve • • • • • • F*Dose/tau = Ass,avg * k Ass,avg = F*Dose/(tau * k) = (F/k) * Dose/tau Divide by Vd Ass,avg/Vd = (F/(k*Vd)) * Dose/tau Cpss,avg = (F/Cl) * (Dose/tau) – Doesn’t this look familiar? – To keep same Cp,ss avg need to keep Ra the same 5 Real advantage to this • Average not significantly influenced by rate of absorption if give it orally – Unless absorption so slow, that drug not fully absorbed as it passes through the gut • Slow (not instantaneous) absorption – Will not change Cp,ss avg – Dampen out peaks and troughs though 6 If Given Orally 400 300 Amount in Body 200 100 0 0 2 4 6 8 10 12 14 Time in halflives In essence it just “dampens” is out – peak lower, trough higher - but the average is the same 7 Back to Beth R • Beth R (63 yo, k8 kg) is to receive oral multiple dose mexiletine for arrhythmia. It’s clearance is 0.5 L/h/kg and V=6L/kg. It’s recommended to avoid peak to trough fluctuations. Oral dosage forms are 150, 200 and 250 mg and oral bioavalability is 0.9. If want average plasma conc to be 1 mg/k with peak to trough of 0.75-1.5 ml/L what is appropriate dosing regimen? Beth Again • • • • • • • Cp, avg = 1 mg/L Cl = 0.5 L/hr-kg * 58 kg = 29 L/hr Vd = 6 L/kg * 58 kg = 348 Cpss,avg = (F/Cl) * Dose/tau = 0.9/29 * (Dose/tau) 32.2 mg/hr = (Dose/ 8 hr) 257.6 mg q8hr (so pick the 250 mg) 9 Beth’s Peak and Trough • Approximate it! • Know average concentration and dose – Assume peak = average plus ½ dose – Assume trough = average minus ½ dose – (APPROXIMATION!! Not too bad if tau<t1/2) 10 Beth’s Peak and Trough • Ass, avg = 1 mg/L * 348 = 348 mg (total) • Peak = 348 + ½ dose =348+125 = 473mg/ 348L 1.25 mg/L • Trough=348 – ½ dose = 48 – 125=223mg/ 348L 0.64 mg/L 11 All other things being the same • Cpss,avg = (F/Cl) * (Dose/tau) • Don’t care about fluctuation per se • Dosage Rate - 160 mg/d – 80 mg twice a day – 160 mg once a day – 320 mg every other day – 1120 mg once a week • Compliance, toxicity, irritation etc. 12 How Long to Steady State • Based on half-life – t ½ = 0.693/k or t ½ = 0.693 * (Vd/Cl) – 50% in one half life – 90% in 3.3 half lifes – Determine relative to number of doses • N (50%) = 0.693/(k*tau) • N (90%) = 2.3/ (k*tau) 13 So you might want a loading dose • Just a different way of looking at this • Don’t figure out maintenance dose and then back track to get the loading dose • Give a loading dose that will be therapeutic and then figure out maintenance dose needed to keep you there • Not MDLD but really LD MD 14 LD - MD • Loading Dose LD gets to therapeutic levels • A t1= LD (or Cp = LD/Vd) • Then it decays before next dose, and next dose (e.g. MD) needs to replace the lost drug • A t2 = LD * e –k*tau • So • MD = (At1-At2) = LD – LD * e –k*tau 15 LD and MD • MD = (At1-At2) = LD – LD * e –k*tau = LD * (1-e-k*tau) – Or as a ratio • MD/LD = (1-e-k*tau) – This shouldn’t be surprising – Ratio depends solely on – elimination k and tau • If drug given every t ½ - MD is one-half LD 16 • If drug given every 2 t ½ - MD is one-quarter LD What if a dose is skipped? 350 300 250 Amount in Body 200 150 100 50 0 0 2 4 6 8 10 12 14 Time (in half-lives) - Once a Day if Half-Life = 1 day Gray Bars – normal range 320 down to 160 Skip a dose – blood level at 160 when skipped continued to decline for another half-live to 80 17 What if a dose is skipped? 350 300 250 Amount in Body 200 150 100 50 0 0 2 4 6 8 10 12 14 Time (in half-lives) Giving dose twice a half-life - gray area is range from once a half life dosing Skip a dose – not as big an effect - blood level higher when skipped (less fluctuation – why) - time of next dose is only half of a half-life away 18 And if you skipped two?? 350 300 250 Amount in Body 200 150 100 50 0 0 2 4 6 8 10 12 14 Time (in half-lives) Even is two doses are skipped blood levels a little better than with once-a-half life regime 19 Bottom Lines-Multiple Dosing • Avg blood levels = F/Cl * RA (i.e. Dose/tau) • At steady state– Each dose replaces amount eliminated – Ass,max*e-k*tau + Dose = Ass,max • Exponential Relationships – Cpmax,ss/Cp,max 1st = 1/(1-e-k*tau) – Inverse relation – fluctuation and accumulation 20 Problems • Oral diuretic – chlorthalidone in a 70 kg man • F=0.64, Vd=280L, Cl = 4.5 L/hr • Assume instance absorption • 50 mg/day given (at breakfast) – Accumulation ratio – Max, min amounts in body (at plateau) – Max,min plasma concs in body (at plateau) – Time to achieve 50% plateau – Loading dose? 21 ...
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This note was uploaded on 08/26/2010 for the course PHRM 231 taught by Professor N/a during the Fall '07 term at UConn.

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Multiple+Dosing+II - Multiple Dosing 1 Frequency of...

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