**Problem 5**

Drug clearance must always be adjusted for alterations of renal function using the formula: rfpt = 1 - fenl (1 - rfxpt),where fenl = fraction of the drug excreted unchanged in normal individuals, rfpt = adjustment factor for total clearance in patient, rfxpt = patients' clearance as a fraction of normal clearance and Clnl= normal clearance.

Given that an asthmatic patient has a creatinine clearance of 40mlmin-1 70kg-1 and that the fraction of terbutaline excreted unchanged, fenl= 0.56, the normal clearance,Clnl = 3.4 ml/min/kg, calculate the clearance of the drug in the patient.

#### **Solution**

The patient has depressed renal function: rfxpt = (40 ml/min)/ (120 ml/min) = 0.33

rfpt= 1 - fenl(1-rfxpt)

inline formula rfpt=1-0.56 (1-0.33) = 0.62

inline formula Clpt= Clnl.rfpt = 3.4ml.min-1kg-1x 0.62 = 2.1ml.min-1kg-1

Problem 6

istration of ampicillin or amoxicillin causes a skin rash which resembles the one caused by penicillin hypersensitivity. The ampicillin-caused rash can be distinguished from penicillin hypersensitivity on the basis of two features; it has a later onset, typically ten to fourteen days, compared to penicillin sensitivity which comes between seven to ten days. Furthermore, the sensitivity does not recur following re-exposure to ampicillin and is not as serious as the one

The two basic approaches for clinical evaluation of adverse drug reactions include the cohort studies (or follow-up studies) of patients taking the drug and the case control studies which

In cohort studies, drugs are identified and incidences of adverse effects recorded. The weak‐ nesses of these studies include; the relatively small number of patients likely to be recruited, and lack of suitable control groups to assess the background incidence of any apparent adverse

The approach here is to start with the incidence of adverse reaction(s) and then look for the drug and the individuals with symptoms which could be due to an adverse drug reaction. These individuals are screened to see if they had taken the drug. The prevalence of drug taking in the group is then compared with the prevalence in a reference population which did not take the drug. This approach is excellent for validation and assessment of adverse drug effects, but it may not detect new adverse effects. Furthermore, it requires a very large number of patients and is very expensive to undertake hence difficult to justify and organize for every

Drug clearance must always be adjusted for alterations of renal function using the formula: rfpt = 1 - fenl (1 - rfxpt),where fenl = fraction of the drug excreted unchanged in normal individuals, rfpt = adjustment factor for total clearance in patient, rfxpt = patients' clearance as a fraction of

Given that an asthmatic patient has a creatinine clearance of 40mlmin-1 70kg-1 and that the fraction of terbutaline excreted unchanged, fenl= 0.56, the normal clearance,Clnl = 3.4

The patient has depressed renal function: rfxpt = (40 ml/min)/ (120 ml/min) = 0.33

caused by penicillin.

512 Drug Discovery

reaction noted.

new product.

**Problem 5**

**Solution**

rfpt= 1 - fenl(1-rfxpt)

**14.21. Worked examples**

normal clearance and Clnl= normal clearance.

ml/min/kg, calculate the clearance of the drug in the patient.

**Cohort or prospective studies**

**Case control or retrospective studies**

**14.20. Clinical evaluation of adverse drug reactions**

record the incidences of adverse drug effects retrospectively.

Given the following characteristics of drug A; t½ = 8h, given at a dosage of 450mg every 12h, has Vss = 0.5 L/kg, effective concentration is 12mg/L and that

$$\mathcal{C}\_{ss}\min = \frac{F \ge \text{dose} / V\_{ss} \text{(exp}^{-kt})}{1 - \exp^{(\text{-}KT)}}$$

$$\mathcal{C}\_{ss'}\max = \frac{\text{F} \ge \text{dose} / \mathcal{V}\_{ss}}{1 - \exp^{(\text{-}kT)}}$$

Determine the Cssmin and Cssmax for a 60 kg patientif F = 1 and expKT = 0.35. Explain how changing of the dosage interval to 6 hours would affect Cssmin.

#### **Solution**

The term exp(-KT) is the fraction of the last dose that remains in the body at the end of a dosing interval and is equal to 0.35 and Css min = Css max.exp(-kt). Therefore,

$$\text{C}\_{\text{ss}}\text{min} = \frac{450/30 \times 0.35}{1 \cdot 0.35} \text{=} 15/0.65 \times 0.35 \sim 8.0 \text{ mg/L} \text{ while } \text{C}\_{\text{ss}}\text{max} = 15/0.65 = 23 \text{ mg/L}$$

The predicted minimum of 8.0mg/L is below the effective concentration to achieve efficacy. Therefore the dosing interval should be reduced. A reduction of the interval to, say, six hours, increases denominator and therefore causes an increase of Cssmin. Since t1/2 = 0.693/K, K = 0.086 i.e. 1 - e-KT = 1 - 2.71-0.086 x 6 = 1 - 0.596 = 0.4.

The new Css minimum becomes; = 450/30 x 0.4 = 15 mg/L which is within the required thera‐ peutic concentration.

#### **Review exercise**


**4.** Given that fenl for drug X = 0.42, and the normal creatinine clearance is 120 ml/min/70 kg, calculate the clearance rate of the drug by a patient with creatinine clearance of 75 ml/min/ 70 kg.

[11] Timothy, D. R., Steven R.G., Herve, T., Brian A.D. (2001). Finding drug targets in

Introduction to Biochemical Pharmacology and Drug Discovery

http://dx.doi.org/10.5772/52014

515

[12] Tim, R. C. and Marc L. (2007). Pharmacogenitics of antiretroviral drugs for the treat‐ ment of HIV-infected patients: An update. Infection, Genetics and Evolution 7, 333-342

[13] Turnheim, K. (2003). Why drug therapy gets old Pharmacokinetics and pharmacody‐

[15] Ulrich, R., Friend, S. H. (2000). Toxicogenomics and drug discovery: Will new technol‐

[16] Werbovetz, K. A. (2000). Target based drug discovery for Malaria, Leishmania and

[17] Aungst B. (2000). Intestinal permeation enhancers*. Journal of Pharmacological Sciences,*89

[18] Salama, N.N. Eddington N.D. Fasano, A. (2006).Tight junction modulation and its relationship with drug delivery. *Advanced Drug Delivery Reviews*.58: 15-28.

[19] Guengerich F. P. (2001). Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. *Chemical Research and Toxicology.*14: 611 - 650.

[20] Blanka R., (1998). Receptor-mediated targeted drug or toxin delivery. *Advanced Drug*

[21] John R. C. (2005). Some distinctions between flavin-containing and cytochrome P450monooxygenases.*Biochemical and Biophysical Research Communications* 338: 599-604.

[22] Xiaoling L. William K. C. (1999). Transport, metabolism and elimination mechanisms

[23] Brown, M.J., Bennet, P.N., Lawrence, D.R. (1997). Clinical pharmacology (8th Edition)

[24] Hardman J.G., Gilman A.G., Limbird L. E.(1996). *The pharmacological basis of therapeu‐*

[25] Katzung B. G.,(2004). *Basic and clinical pharmacology* (9th Edition) Mcgraw Hill Inc.

of anti-HIV agents. *Advanced Drug Delivery Reviews*29: 273-289 39, 81-103.

[14] Paul, B. (2003). Toxicokinetics in preclinical evaluation*. Research Focus* DD Vol. 8

ogies help us produce better drugs? *Nat. Rev. Drug Discov.* 1, 84 – 88.

Trypanosomiasis. C*urrent medicinal Chemistry* 7 (8) 835 – 860.

(4), 429-442.

*Delivery Reviews* 29: 273-289.

Wesley, Longman China Ltd.

*tics* (9thEdition) McGraw-Hill.

microbial genomes. *Drug Discovery Today*6, (17): 887-892.

namics in the eldery. *Experimental Gerontology* 38 843-853.

**5.** Write an essay on adverse drug reactions associated with the use of macrolide antimicro‐ bial agents.
