Determination of dose and dosing interval
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The document discusses several key points about determining appropriate drug doses and dosing intervals: 1. The starting dose and dosing interval should aim to deliver a desirable therapeutic drug level based on the drug's pharmacokinetic parameters and objectives. 2. For many drugs, literature provides therapeutic drug levels and pharmacokinetics to guide dosing decisions. In some cases, necessary assumptions must be made when information is incomplete. 3. The dosage regimen is usually calculated to maintain average steady-state blood levels within the therapeutic range, as defined by a standard equation provided. Adjusting dose and interval impacts peak and trough concentrations.
Determination of dose and dosing interval
- 1. Determination of Dose and Dosing Interval Dr. Ramesh Bhandari Asst. Professor Department of Pharmacy Practice KLE College of Pharmacy, Belagavi
- 2. Dr.RameshBhandari Asst.Professor Calculation of the starting dose of a drug and dosing interval is based on the objective of delivering a desirable (target) therapeutic level of the drug in the body. For many drugs, the desirable therapeutic drug levels and pharmacokinetic parameters are available in the literature.
- 3. Dr.RameshBhandari Asst.Professor However, In some cases, literature may not have complete drug information then, pharmacokineticist must make certain necessary assumptions in accordance with the best pharmacokinetic information available.
- 4. Dr.RameshBhandari Asst.Professor For a drug that is given in multiple doses for an extended period of time, the dosage regimen is usually calculated to maintain the average steady-state blood level within the therapeutic range and given by following equation: C∞ av = 1.44D0t1/2F Vd τ
- 5. Dr.RameshBhandari Asst.Professor Examples: 1. Pharmacokinetic data for clindamycin were reported by DeHaan et al (1972) as follows: K=0.247h-1, t1/2=2.81h, Vd=43.9L/1.73M2 What is the steady-state concentration of the drug after 150 mg of the drug is given orally every 6 hours for a week? (Assume the drug is 100% absorbed.)
- 6. Dr.RameshBhandari Asst.Professor Solution: C∞ av = 1.44D0t1/2F Vd τ C∞ av = 1.44x1,50,000x2.81x1 43900x6 C∞ av = 2.3mcg/ml
- 7. Dr.RameshBhandari Asst.Professor Example: 2 2. According to Regamey et al (1973), the elimination half-life of tobramycin was reported to be 2.15 hours and the volume of distribution was reported to be 33.5% of body weight. What is the dose for an 80-kg individual if a steady-state level of 2.5 μg/mL is desired? Assume that the drug is given by intravenous bolus injection every 8 hours
- 8. Dr.RameshBhandari Asst.Professor Determination of Both Dose and Dosage Interval Both the dose and the dosing interval should be considered in the dosage regimen calculations. For Intravenous multiple-dosage regimens, the ratio of C∞ max / C∞ min may be expressed by:
- 9. Dr.RameshBhandari Asst.Professor C∞ max = C0 p/(1 - e-k τ) C ∞ min C0 p e-k τ (1 - e-k τ) C∞ max = 1 C∞ min e-k τ From above equation, a maximum dosage interval (τ), may be calculated that will maintain the serum concentration between desired C ∞ min and C ∞ max. After the dosage interval is calculated, then a dose may be calculated.
- 10. Dr.RameshBhandari Asst.Professor Example:1 The elimination half-life of an antibiotic is 3 hours with an apparent volume of distribution equivalent to 20% of body weight. The usual therapeutic range for this antibiotic is between 5 and 15 μg/mL. Adverse toxicity for this drug is often observed at serum concentrations greater than 20 μg/mL. Calculate a dosage regimen (multiple IV doses) that will just maintain the serum drug concentration between 5 and 15 μg/mL.
- 11. Dr.RameshBhandari Asst.Professor Solution: Determine the maximum possible dosage interval (τ). Determine the dose required to produce from C∞ max C∞ max = D0 / Vd 1 – e-Kτ
- 12. Dr.RameshBhandari Asst.Professor Effect of changing dose and dosing interval on C∞ min, C∞ max and C∞ av. During intravenous infusion, Css may be used to monitor the steady-state serum concentrations. When considering TDM of serum concentrations after the initiation of a multiple-dosage regimen, the trough serum drug concentrations or C∞ min may be used to validate the dosage regimen.
- 13. Dr.RameshBhandari Asst.Professor The blood sample withdrawn just prior to the administration of the next dose represents C∞ min. To obtain C∞ max , the blood sample must be withdrawn exactly at the time for peak absorption.
- 14. Dr.RameshBhandari Asst.Professor In practice, an approximate time for maximum drug absorption is estimated and a blood sample is withdrawn. Because of difference in absorption rate, C∞ max obtained is only approximation rather than true value. So the C∞ av is used most oftenly for dosage calculation.
- 15. Dr.RameshBhandari Asst.Professor The advantage of using C∞ av as an indicator for deciding therapeutic blood level is that C∞ av is determined on a set of points and generally fluctuates less than either C∞ max or C∞ min. Moreover, when the dosing interval is changed, the dose may be increased proportionally, to keep C∞ av constant.
- 16. Dr.RameshBhandari Asst.Professor In general, if a drug has a relatively wide therapeutic index and a relatively long elimination half-life, then flexibility exists in changing the dose or dosing interval (τ), using C∞ av as an indicator. When the drug has a narrow therapeutic index, C∞ max and C∞ min must be monitored to ensure safety and efficacy.
- 17. Dr.RameshBhandari Asst.Professor As the dose or dosage intervals change proportionately, the C∞ av may be the same but the steady state peak, C∞ max , and trough, C∞ min , drug levels will change. C∞ max is influenced by the dose and the dosage interval. An increase in the dose given at a longer dosage interval will cause an increase in C∞ max and a decrease in C∞ min.