Plasma Concentrations After An Extravascular Dose Half-Life Physiological Determinants: Plasma Concentrations During An Intravenous Infusion Assignment, USA, Australia

Equations and physiological values

Glomerular filtration rate = 120 mL/min
Hepatic blood flow = 1.5 L/min
Renal blood flow = 1.2 L/min
Cardiac output = 5 L/min
Haematocrit = 0.5

Plasma concentrations after an intravenous bolus
– monoexponential C = C(0).exp-k.t
– biexponential C = A.exp-.t + B.exp-.t

Plasma concentrations during an intravenous infusion (monoexponential only)
C = (Ro/CL).(1-exp(-k.t))

where Ro is the zero-order infusion rate

Plasma concentrations after an extravascular dose Half-life Physiological determinants of clearance and volume of distribution Hepatic clearance Renal clearance Volume of distribution Pharmacodynamic response Accumulation Index Serenel® is a new amphetamine-like compound being developed for use in the treatment of attention-deficit hyperactivity disorders and related conditions. The drug is a weak base with a pKa of 8.8. In a first-time-in-man Phase 1 study, the drug was administered as a single intravenous bolus (50mg) and a single oral dose (50mg) to healthy adult males (18-30 years of age). The oral dose consisted of a dry powder placed inside a gelatin capsule. The following mean plasma concentration-time data were obtained.

Urine was collected for 24 hours after intravenous dosing and was found to contain 40 mg of unchanged drug and 8mg of a metabolite.

Question 

1. (a) Plot the data, and

(b) Calculate the following pharmacokinetic parameters

(i) the Elimination half-life

(ii) Volume of distribution (referenced to plasma)

(iii) Clearance (referenced to plasma)

(iv) Renal Clearance (referenced to plasma) after the intravenous dose

(c) Determine the equation that describes the plasma concentration versus time profile of the drug after oral administration. Give your answer in the following format:
C = A(e-x.t – e-y.t)

(d) Calculate the absolute bioavailability of the drug after administration of the oral capsule

(e) Given that the fraction of drug unbound in plasma is 0.23, determine the likely mechanisms involved in the renal excretion of this drug.

(f) On the basis of your answers to the above questions and the known
physicochemical properties of the drug, provide some predictions about how the following factors might alter the pharmacokinetics of the drug (including the likely effect on clearance, the volume of distribution, and half-life.

(i) An increase in urine pH

(ii) Induction of hepatic enzymes involved in the oxidation of the drug

(iii) Displacement of the drug from plasma binding sites

(iv) Coadministration of the drug cimetidine, which is an inhibitor of hepatic drug metabolism and is able to inhibit the renal tubular secretion of organic cations.

2. Mexiletine is an antiarrhythmic agent with the following pharmacokinetic
properties:

Clearance = 5.02 mL/min/kg

Volume of Distribution = 3.46 L/kg

(a) If mexiletine was given by repeated intravenous bolus doses, of 200mg every 8 hours, to a 60-kg patient calculate the plasma concentration:

(i) just after the first dose (Cmax) mg/L

(ii) at the end of the first dose interval (Cmin) mg/L

(iii) just after a dose at steady state (Cmax, ss) mg/L

(iv) just before a dose at steady state (Cmin, ss) mg/L

(b) If mexiletine was infused at a constant rate of 25mg per hour, what would be the plasma levels after

(i) 8 hours

(ii) 16 hours

(iii) at steady state

(c) If mexiletine was given as a bolus dose of 400mg and then infused continuously at a rate of 20mg per hour, how would the plasma concentration versus time curve appear (provide a sketch and show your calculations below).

(d) For what reason would a drug be administered as a fast infusion rate for a short time followed by a slower infusion rate thereafter, as in the example given in part (b)

3. Describe the factors that can vary the rate of gastric emptying. Explain how these factors can influence the oral absorption of a drug (give examples where possible).

4. The following pharmacokinetic parameters and properties have been elucidated for a drug (CDR I) being developed for the treatment of dementia of the Alzheimer’s type. The drug is a weak acid with a pKa of about 4.3

• Volume of distribution 70 L

• Clearance 2 L/hour

• Renal clearance 1.98 L/hour

• Absolute oral bioavailability of a compressed tablet 0.2

• Desired plasma level 0.1 mg/L

• Molecular weight 198 g/mole

• Solubility in the water of unionized species 1 in 500

Provide answers to the following questions in the spaces provided. Your answers will be marked according to clarity and relevance as well as the accuracy of the content.

(a) Briefly explain what factors are likely to contribute to this drug having a poor oral bioavailability and those factors that are unlikely to be involved.

(b) In evaluating whether this drug would be a suitable candidate for transdermal drug delivery, what factors would you consider, and on the basis of the information provided, what would be your assessment for CDR I?

5. The following questions will draw on your knowledge and understanding of the areas of metabolite kinetics, non-linear pharmacokinetics, and pharmacological response. Please answer the questions clearly and precisely.
Alprenolol is a beta-blocker that decreases the normal increase in heart rate that occurs in response to exercise. It does this by blocking the beta adrenoreceptors in the heart. Alprenolol is a drug with good absorption but low bioavailability (F = 0.2) due to extensive first-pass hepatic metabolism. Its main metabolite is pharmacologically active and also exhibits beta-blocker activity similar to alprenolol. The half-life of alprenolol is about 1-2 hours.

(a) The following figure shows the effect of alprenolol on exercise heart rate in
humans. The graph suggests that the drug is more potent after oral administration than after intravenous dosing. Provide a possible explanation for these findings.

(b) The following graph shows that with increasing dose of oral alprenolol (50, 100, and 200mg) there is a greater than proportional increase in plasma concentration (left panel). Despite this, the effects of the three doses on exercise heart rate are quite similar.

Provide brief possible explanations for:

(i) the non-linear pharmacokinetics of alprenolol (with increasing dose)

(ii) the small increase in drug effect despite the large increase in plasma concentration (with increasing dose)

(iii) why the effects of the drug have not disappeared by 7 hours (after dosing) even though the plasma levels have returned to zero