Pharmacokinetic understanding for liver adjustments

Dear Naveed,

Kindly find this article regarding the effect of cirrhotic liver disease on drug metabolism through CYP system. This can give a general idea as chronic damage will have more profound effect than acute one unless the latter is a fulminant case.

Generally speaking, Dengue fever, by itself; necessitates supportive therapy rather than medications that require adjustment. For other medications that the patient may be already using like antihypertensives, antidiabetics and so on, I think that you can:-

1- Consider the specific drug monograph especially for extensively eliminated medications and adjust accordingly as mentioned earlier

2- Monitor clinical response of the patient and adjust accordingly, e.g BP, Glucose level,…

3- Avoid hepatotoxic medications and replace with safer ones

4- Consider alternatives for medications that are extensively eliminated hepatically, e.g Opiates, NSAIDs, Benzodiazepines….

To conclude, my opinion is that the effect of acute hepatic disease on CYP metabolism will depend on severity and duration (Chronic VS Acute) with probable lesser effect in case of mild short-term acute cases which may call for dose titration, starting with lower dose; with vigilant and clinically based judgment considering drug specific metabolism profile. This is evidenced by the referenced recommendations of no change in drug dosages in mild to moderate liver disease in many hepatically eliminated drugs.

Any further concerns are most welcomed.

My Best Regards,

Thank you for your inquiry which I hope to be able to address.

Hepatic adjustment is usually based on manufacturer recommendations from clinical studies unlike that of Creatinine Clearance for evaluating kidney function.

To make it easy for understanding, let’s refer to the basics of renal drug adjustment: –

        1-      Creatinine, a metabolite of muscle creatine; is solely excreted by kidney

        2-      Renal elimination of creatinine is mainly determined by GFR

        3-      Using Creatinine Clearance can be a reliable measure for kidney function as it relies mainly on one variable        which is GFR

        4-      The clearance of renally excreted drugs is also dependent mainly on GFR rather than other renal ways like secretion

        5-      Thus, using CrCl can be a simple and effective way of adjusting the doses of renally excreted drugs in renally    impaired patients

On the other hand, hepatic impairment can affect all stages of drug pharmacokinetics: –

1-      Absorption: – Through affecting GI function

2-      Distribution: – Through affecting albumin production and associated protein binding of some drugs

3-      Metabolism: – Impairment of CYP system

4-      Excretion: – Through affecting bile production. It may also affect kidney function.

These factors are complex, when compared to the single GFR factor associated with kidney failure.

Thus, it’s advised to include hepatic impairment during the clinical studies for medications to get a more reliable idea about the required adjustment and relate it to the numerical value obtained from classification systems (Child – Pugh, MELD,….) .

To conclude: –

       1-      Severity of liver disease is usually estimated through Child-Pugh classification which incorporates many factors compromised by hepatic failure. Other equations are also developed, yet; Child – Pugh is still the most frequently used.

       2-      Drug adjustment in hepatic disease is complex and requires more investigation during the clinical studies in order to get better insight about the recommended doses. Always refer to the specific drug monograph.

       3-      Generally speaking, high extraction ratio (removed extensively by liver) drugs can be roughly reduced by 50% while those with low extraction ratio can be reduced by 25%. In both cases, close monitoring of effects and side effects is advised.

        4-      Attached: –

1. A)Guidance for industry by FDA for including hepatic impairment as a dosing guideline.
2. B)Review article about Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction.

I hope that this answers your query.