PHA Spring First Exam. 8 Aminoglycosides (5 points)

Transcription

1 PHA 5128 Spring 2012 First Exam 1 Aminoglycosides (5 points) 2 Aminoglycosides (10 points) 3 Basic Principles (5 points) 4 Basic Principles (5 points) 5 Bioavailability (5 points) 6 Vancomycin (5 points) 7 Basic Principles/Bioavailability (10 points) 8 Aminoglycosides (5 points) 9 Antibiotics (5 points) 10 Aminoglycosides (10 points) 11 Vancomycin (5 points) 12 Basic Principles (10 points) 13 Basic Principles (10 points) 14 Basic Principles (10 points) Total Points: 100

2 Question 1 (5 points) Which regimen (dose and dosing interval) will you recommend for amikacin to treat a patient (CL=83.33 ml/min, Vd=0.25 L/kg, 60 kg) that suffers from a pulmonary infection if the true peak and trough concentrations at steady state are supposed to be 30 mg/l and 5 mg/l, respectively? Assume a short term infusion over 30 minutes. A. 650 mg, Q6h B. 650 mg, Q8h C. 425 mg, Q6h D. 425 mg, Q8h E. Not enough information is provided to answer the question Hence,

3 Question 2 (10 points) A 45-year-old female patient (50 kg, 5 4, C p,creat = 1.1 mg/dl,) is treated with 100 mg gentamicin i.v. short-term infusions (T = 30 min) Q8h. Assuming linear pharmacokinetics (Vd=0.25L/kg, CL=Cl Cr ), predict the true peak concentration at the end of the infusion and the true trough concentration before the next infusion at steady state. A. C max : 8.79 mg/l C min : 1.41 mg/l B. C max : 6.79 mg/l C min : 0.85 mg/l C. C max : 8.79 mg/l C min : 1.85 mg/l D. C max : mg/l C min : 0.85 mg/l TBW= 50 (kg) is smaller than IBW*120%, use TBW to calculate the Cl cr

4 Question 3 (5 points) How will an increase in tissue binding affect the AUC, C max, Clearance and half-life (t 1/2 ) of a high-extraction drug? (Please note that means no change) (10pts). A: AUC, Clearance C max, t 1/2 B: AUC, Clearance, C max, t 1/2 C: AUC, Clearance, C max, t 1/2 D: AUC, Clearance, C max, t 1/2 E: None of the options above

5 Question 4 (5 points) An investigational new drug is eliminated entirely by liver (hepatic) metabolism, with a clearance of 75 L/hr in subjects with an average liver blood flow of 80 L/hr. What will be the approximate clearance range in a congestive heart failure patient with a liver blood flow of 60 L/hr but no change in hepatic extraction ratio? A) 52~54 L/hr B) 54~56 L/hr C) 56~58 L/hr D) 58~60 L/hr E= CL int *fu/ (QH + CL int *fu ) CL = QH *E = QH * CL int *fu/ (QH + CL int *fu ) 75 = 80 * CL int *fu / (80 + CL int *fu ) Solving this we get CL int *fu =1200 L/hr Now with new liver blood flow of 60 L/h QH (new) =1 L/h E(new)= CL int *fu/ (QH (new) + CL int *fu ) E(new)= 1200/( ) =0.952 Clhep= 60* = 57.14L/hr However with such a high extraction ratio, one could assume negligible change in its value with the decreased liver blood flow and assume it to remain same and may use the following method: Clhep = QH * E E = Clhep /QH = 75 /80 = For CHF patient: QH = 60 L/hr Clhep = QH *E = 60 *0.938 = 56.25L/hr

6 Question 5 (5 points) In general, what is NOT the reason an oral dosage form will have <100% bioavailability: A) Poor solubility/dissolution rate B) First-pass effect C) Poor permeability D) Low volume of distribution

7 Question 6 (5 points) KT, a 40-year-old, 5 9, 70 kg woman with a serum creatinine of 1.5mg/dL, has been started on 1.5g of vancomycin over one hour short-term infusion every 12h for the treatment MRSA skin infection. What are the initial peak and trough vancomycin concentrations: A) 38.6mg/L; 14.6 mg/l B) 36.4 mg/l; 15.4 mg/l C) 40.9 mg/l; 13.9 mg/l D) 37.1 mg/l; 16.1mg/L Vd= 0.17 age TBW +15 = = 37.2 L IBW = (height in inches-60) kg = =66.2 kg 120%IBW = = 79.4 kg > TBW Use TBW to calculate CL Cr CL CL Cr (140 age) weight 85Cp creat (140 40) mL/ min L / h k e CL Vd 3.294L / h L h C peak D (1 e CL ket ) 1500 (1 e ) 38.57mg / L C trough = C peak e -ke (τ-t) = e = mg/l

8 Question 7 (10 points) The following figures are plasma concentration time profiles for Drug X after oral administration (figure 1 is in normal scale and figure 2 is in log-scale). The data are from a healthy subject (p1) and a patient with congestive heart failure (p2). Figure 1 Figure 2 So comparing to the healthy subject (p1), which statement about the PK parameters of the patient with congestive heart failure (p2) is NOT correct A B C D E CL/F will decrease AUC will decrease C max will increase T max will not change T 1/2 will not change

9 Question 8 (5 points) Which of the following statement(s) is/are false regarding aminoglycosides? i. Hepatic metabolism is responsible for the elimination of the aminoglycosides. ii. Peak concentration for Amikacin is in the 5-8 mg/l range whereas Gentamicin peak concentration is in the mg/l range in people with normal renal function. iii. Since aminoglycosides and creatinine clearances are similar over a wide range of renal function, aminoglycoside clearance can be estimated from the formulas used to estimate creatinine clearance when concentrations are within the therapeutic range. iv. Clinical peak and trough concentrations can be used to compute the volume of distribution v. Clinical peak and trough concentrations can be used to compute the dosing interval but adjustments are required. A. I, II, III B. I, II, IV C. III, IV, V D. II, IV, V E. I, II Answer: (E)

10 Question 9 (5 points) Which of the following statements is/are true regarding ceftazidime? (see graph below). The graph below shows the efficacy parameters of ceftazidime against K. pneumonia infection in neutropenic mice. The target level for efficacy is 7.2 log 10 CFU/Thigh at 24 hours. i. The effect profile for this drug is a concentration-dependent one. ii. The time above MIC is the parameter of choice to evaluate efficacy of ceftazidime against K. pneumonia. iii. The parameter value that achieves the minimum effect is approximately 35 hr above MIC, which corresponds to the target of 7.2 log 10 CFU/Thigh. iv. The 24-hour AUC/MIC ratio greater than 1000 is required to achieve the effect of lowering the log10 CFU/Thigh below 7.2. v. Increasing the time above MIC, peak drug concentration and AUC/MIC ratio resulted in a decrease in CFU suggests that this drug has bactericidal effect. A. I, IV, V B. II, III, V C. II, III D. II, III, IV, V E. I, III, IV Answer: (D)

11 Question 10 (10 points) Gentamicin, after IV bolus administration, exhibits a triphasic distribution characterized by the following equation: Conc( t) Aexp( t ) Bexp( t) C exp( t). If the half-lives for the the α-, -, and -phases are 20 minutes, 2.5 hours and 45 hours, respectively, estimate the parameter values for α,, and in hr -1. A h -1, h -1, h -1 B h -1, h -1, h -1 C. 0.4 h -1, 0.05 h -1, h -1 D h -1, h -1, h -1 E. 3 h -1, 0.4 h -1, h -1 Answer: (B) Solution: Using the equation h (20 / 60) h h 2.5h h 45h 0 1 ln(2) k, t 1 2

12 Question 11 (5 points) A female patient, 65 years of age, 5 1 in height and 110 lbs in weight acquired S. pneumonia. Her serum creatinine is 0.65 mg/dl. The MIC of vancomycin against her infection was estimated in the laboratory to be 2.0 g/ml. Use the vancomycin dosing nomogram table to determine the patient s dosing regimen. Compute both C ss, max and C ss, min based on IV bolus administration for this dosing regimen. Do you need to adjust the dosing frequency based on the computation that you have obtained, so that the C min,ss is greater than 15 mg/l? Detroit receiving Hospital and University Health Center vancomycin dosing nomogram table Useful information: 1 kg = 2.2 lbs A. 500 q12h, C min,ss = 4.92 mg/l, C max,ss = mg/l. Since the trough is below 15 mg/l, you need to either decrease the dosing interval or increase the dose. B. 500 q8h, C min,ss = mg/l, C max, ss = mg/l. No need to adjust the recommended dosing regimen. C q12h, C min,ss = mg/l, C max,ss = mg/l. No need to adjust the recommended dosing regimen. D q8h, C min,ss = mg/l, C max, ss = mg/l. No need to adjust the recommended dosing regimen. E. 500 q12h, C min,ss = 4.92 mg/l, C max,ss = mg/l. Since the trough is below 15 mg/l, you need to either decrease the dosing interval or increase the dose. Answer: (A)

13 110 lbs = 50 kg; age=65 years; height = 61 Use the following equation to compute the volume of distribution: V d (in L) = 0.17(age in years) (TBW in kg) + 15 V d = L IBW *( height in inches 60) *(61 60) 47. 3kg We will use the TBW since TBW is less than 120% of IBW. (140 Age)( TBW in kg) CLCr for female ml/ min (85)( SCr in mg / dl) CL Cr ( yr)(50kg) 67.87mL/ min 85(0.65) Vancomycin CL ~ CL Cr Based on the nomogram, you will use 500 q12h dosage regimen. 1L 60min ml / min * * 4.07 L / hr 1000mL 1hr K t e 1 2 CL V d 4.07L / hr L ln 2 6.3hr hr 1 For IV bolus, S F dose 1 1(1)(500mg) 1 Cmax, ss V 1 exp( k ) 37.05L 1 exp( 0.11hr C min, ss C d max, ss exp( k ) 18.41mg / L*exp( 0.11hr ss hr) 4.92mg / L 18.41mg / L 12hr)

14 Question 12 (10 points) Calculate the clinical peak and trough concentrations at steady state after administration of 1250 mg drug A via multiple short-term infusions (infusion time = 1 h, dosing interval = 12 h). The clinical peak is defined as the plasma concentration 30 min after the end of an infusion. The clinical trough is defined as the plasma concentration 30 min before the start on an infusion. Drug A is known to follow a one-compartment body model and shows linear pharmacokinetics. The clearance and volume of distribution of drug A are 20 L/h and 60 L, respectively. Round appropriately. A B C D E and 0.55 mg/ml 30.5 and 1.1 mg/l 30.5 and 1.1 mg/ml 30.5 and 1.1 g/l and 0.55 mg/l

15 Question 13 (10 points) Drug B is administered via multiple short-term infusions. Determine an appropriate dosing regimen (dosing rate (R 0 ) and dosing interval) of drug B to achieve desired steady state plasma concentrations of 12.5 mg/l for the peak (drawn 2 h after the end of a 2 h infusion) and approximately 3.5 mg/l for the trough. Assume that drug B s plasma-concentration-time profile follows a one-compartment body model. (CL = 15 L/h, VD = 100 L). Round appropriately and use a clinically used dosing interval. A B C D E R 0 = 815mg/h Q24h R 0 = 1630mg/h Q12h R 0 = 1630mg/h Q24h R 0 = 815mg/h Q12h R 0 = 815mg/h Q8h

16 Question 14 (10 points) Select the incorrect statement A B C D E In a one-compartment body model, the volume of distribution decreases with an increase in plasma protein binding In a two compartment body model, the volume of distribution at steady state (VD SS ) is always larger than the volume of distribution of the central body compartment (Vc) The plasma concentration at steady state is a function of dosing interval (R 0 ) and clearance (CL) In a two compartment body model, VD area is not independent of the clearance (CL) For a high extraction drug, the free plasma concentration at steady increases with a decrease in tissue protein binding