Dosing Regimen Individualization (DRI)

Individualization incorporates patient’s specific parameters such as age, gender, body weight and height into the PK parameters employed by the system to construct plasma drug levels for any PK scenario. For healthy individuals, the following patient-related specifics or parameters have been used to individualize dosing regimens:

BSA could serve to estimate a new maintenance dose for subject of different ages and/or hight/weights. This will be of particular interest for pediatric subjects.

In cases where actual plasma levels are provided in the system PK-Database, these will be indicated as “Reported Therapeutic Range”. Otherwise, the system will use the population PK metrics to construct a “Theoretical Therapeutic Range”.

The above ranges could be modified by users. Such modification will be directly reflected on the graphical display of the range only. However, modifying any other default PK parameter will only affect the graphical display of the plasma profile. Reflecting such modification on the graphical display of the range band will be an option than may be selected by user. Once the new dosing interval has been determined, the maintenance dose could be estimated as described for different routes of administration.

The availability of an abundance of PK models together with PK metrics most drugs allow theoretical prediction of their plasma levels. Notwithstanding, PK metrics reported for any drug represent average values that may be associated with different levels of variability. Expressed as percent coefficient of variation around mean values, such variability may exceed 70% in some drugs. For example, the biological half-life of carbamazepine could range between 18 to 70 hours. Such variability renders any prediction of plasma level for such drug totally pointless and meaningless. In this regards, therapeutic drug monitoring bears special significance within the context of dosing regimen individualization.

It must be noted that unless a strong association exist between drugs dynamic effect and their plasma levels, predicting such levels could only bear a theoretical significance. Accordingly, users of PK-Works must be cognizant of this important realization and should offer any unfounded interpretation for drugs plasma levels provided by the system.

Age & Weight Related DRI

There are instances whereby clinical practitioners prescribe drugs for individuals on the basis of their age and weight. It may be assume that regular dosing regimens of drugs are generally designed for average body surface area (BSA) which is estimate at \(1.73m^2\) for average subjects or ideal body weight (IBW). It must be noted that IBW is referred to as lean body weight by some references. Alterations in these parameters may require a corresponding alteration in their dosing regimens. Several equations have been suggested for the estimation of these body-related metrics. The oldest of these has been suggested by DuBios [7] in 1916.

This equation is operationally equivalent to another formula suggested by Mosteller [8] in 1986. Devine [9] has also devised an equation for the estimation of IBW that takes into account weight, height and gender: $$BSA_{m^2}=W^{0.425} \times H^{0.725} \times 0.007184$$ $$IBW_{kg}=50+2.3 \times H_{(in)}\dots (M)$$ $$IBW_{kg}=45+2.3 \times H_{(in)}\dots (F)$$ $$BMI=\frac{W_{(kg)}}{(H_{(m)})^2}=\frac{W_{(lb)}\times 703}{(H_{(in)})^2}$$ Estimates of BSA could be used as basis for DRI, or normalization, especially for pediatrics subjects who are administered drugs with known narrow therapeutic index. On the other hand, IBW is often used to normalize dosing regimens for obese individuals whose weight is 30% higher than the normal weight. This is related to the fact that the elimination of many drugs is altered with age. This is mainly caused by liver function which may be underdeveloped in children compared to adult individuals. Also, liver, as well as, kidneys function is likely to deteriorate with age.

DRI could be also undertaken when there is an established and reliable estimate of an altered PK metric. This applies mainly to the age- or disease-related changes in drugs accumulation properties. Clinician tend to use such officially approved information for the individualization od drugs dosing regimens In addition, drug manufacturers are often required, by the regulatory authorities, to avail information on altered PK properties in special population so that clinicians use it as basis for DRI.

Dosing regimen individualization could assume special importance in cases where the elimination of drugs may be influenced by patient’s health condition. It is established that although the cardiac output may influence the elimination of some drug, the main two disease condition that have direct impact on drug clearance are kidneys and/or liver dysfunctions. Hence, PK-Works has been designed to account the alteration in the capacity, or the degree of impairment, of these two organs to eliminate drugs from the body. This will be detailed hereunder:

Renal Impairment

The kidneys represent an important organ in controlling body fluids and electrolytes as well as the elimination the metabolic end products of indigenous and exogenous substances. Any impairment in the kidneys function will lead to accumulation of such substances in the body. The decline in the kidney function will affects the pharmacokinetics of drugs that are partially or totally eliminated by the kidneys. Some of the more common causes of kidney failure include disease, injury, drug induced nephrotoxicity or alteration in the physiological conditions (acidity) of the kidneys. Acute or chronic diseases or of the kidneys can cause uremia, in which glomerular filtration is decrease to varying extents leading to accumulation of fluids and nitrogenous substance in the body. This may further lead to a reduction of glomerular filtration and passive or active secretion of many substances including drugs. Renal impairment may be also caused by disease conditions leading to pyelonephritis, hypertension or diabetes mellitus.

Irrespective of the underlying cause(s) for renal impairment, many test procedures have been devised to assess the degree of such impairment. All such procedures are based on the assessment of renal creatinine or inulin clearance. In this regard, Clcr creatinine clearance is favored due to tediousness of test methods suited to measure inulin clearance. In either of these methods, their estimate clearance values if generally equated with the glomerular filtration of the kidneys.

Glomerular Filtration Rate (GFR)

Cockcroft and Gault [6] have suggested the following procedure for the assessment the kidney function: $$GFR_{(mL/min/1.73m^2)}=186 \times S_{cr}^{-1.154} \times Age_{(yr)}^{-0.203} \dots(M)$$ $$GFR_{(mL/min/1.73m^2)}=186 \times S_{cr}^{-1.154} \times Age_{(yr)}^{-0.203} \times 0.742 \dots(M)$$ Output of the above equation must be multiplied by 1.21 to account for African ethnicity.

This method has become one of the most wildly used methods for estimating the capacity of the kidneys to eliminate substance from the body. While accounting for age, gender and ethnicity, it utilizes serum creatinine levels in estimating the glomerular filtration rate. It is well know that more than 85% is cleared by tubular secretion and minimal amounts are cleared by non-renal routes. It is also established that the production of creatinine in males and females ranges between 20 - 25 and 15 - 20 mg/kg IBW respectively. These value decrease with age at a rate of 2 mg/kg IBW per decade.

Estimated eGFR by Abbreviated MDRD [14] (Modified Diet Renal Disease)

$$GFR_{[mL/min/1.73m^2]}=186 \times SerumCr_{[mg/dL]}^{-1.154} \times Age_{[yr]}^{-0.203} \times Sex \times Ethnicity$$ Equation parameters such as Gender, have two or more discrete values that may be used in the calculation. The numbers in the parentheses, e.g. 0.742, represent the values that will be used.

For creatinine in \(\mu mol/L\): $$eGFR=32788 \times SerumCreatinine^{-1.154} \times Age^{-0.203} \times [1.210 \text{ if Black}] \times [0.742 \text{ if Female}]$$ For creatinine in \(mg/dl\): $$eGFR=186 \times SerumCreatinine^{-1.154} \times Age^{-0.203} \times [1.210 \text{ if Black}] \times [0.742 \text{ if Female}]$$ Creatinine levels in \(\mu mol/L\) can be converted to \(mg/dl\) by dividing them by 88.4. The 32788 number above is equal to 186×88.41.154. A more elaborate version of the MDRD equation also includes serum albumin and blood urea nitrogen (BUN) levels: $$eGFR=170 \times SerumCreatinine^{-0.999} \times Age^{-0.176} \times [1.180 \text{ if Black}] \times [0.742 \text{ if Female}]\times BUN^{-0.170}\times Albumin^{+0.318}$$ Where the creatinine and blood urea nitrogen concentrations are both in \(mg/dl\). The albumin concentration is in \(g/dL\).

These MDRD equations are to be used only if the laboratory has NOT calibrated its serum creatinine measurements to isotope dilution mass spectrometry (IDMS). When IDMS-calibrated serum creatinine is used (which is about 6% lower), the above equations should be multiplied by 175/186 or by 0.94086.

Since these formulae do not adjust for body mass, they (relative to the Cockcroft-Gault formula) underestimate eGFR for heavy people and overestimate it for underweight people.

GFR by Schwartz [15,16] (age less than 18)

$$GFR_{(mL/min/1.73m^2)}=MuscleFactor \times Height_{[cm]}/SerumCr_{[mg/dL]}$$ Equation parameters such as Muscle Factor, have two or more discrete values that may be used in the calculation. The numbers in the parentheses, e.g. 0.33, represent the values that will be used.

The Muscle Factor is directly proportional to the muscle component of the body and varies with the age of the infant or child.

GFR by CKD-EPI [17-19] - Chronic Kidney Disease, Epidemiology Collaboration

$$GFR_{(mL/min/1.73m^2)}=141 \times \min\left(SerumCr_{[mg/dL]}/\kappa,1\right)^\alpha \times \max\left(SerumCr_{[mg/dL]}/\kappa,1\right)^{-1.209} \times 0.993^{Age_{[yr]}} \times Gender \times Ethnicity $$ Equation parameters such as Ethnicity, have two or more discrete values that may be used in the calculation. The numbers in the parentheses, e.g. 1, represent the values that will be used. GFR is estimated by an Equation developed by the Chronic Kidney Disease Epidemiology Collaboration.

For females, the following values are used: \(Gender = 1.018\); \(\alpha= -0.329\); \(\kappa=0.7\). For males, the following values are used: \(Gender = 1\); \(\alpha= -0.411\); \(\kappa=0.9\).

GFR by MDRD [20] - Chronic Kidney Disease

$$GFR_{[mL/min/1.73m^2]}=170 \times SerumCr_{[mg/dL]}^{-0.999} \times Age_{[yr]}^{-0.176} \times Gender \times Ethnicity \times BUN_{[mg/dL]}^{-0.170}\times Albumin_{[mg/dL]}^{0.318}$$ Equation parameters such as Gender, have two or more discrete values that may be used in the calculation. The numbers in the parentheses, e.g. (0.762), represent the values that will be used.

GFR by MDRD [21] - IDMS-Traceable SCr

(IDMS = isotope dilution mass spectrometry) $$GFR_{[mL/min/1.73m^2]}=175 \times StandardizedSerumCr_{[mg/dL]}^{-1.154} \times Age_{[yr]}^{-0.203} \times Gender \times Ethnicity$$ Equation parameters such as Gender, have two or more discrete values that may be used in the calculation. The numbers in the parentheses, e.g. 0.742, represent the values that will be used. This Equation helps estimate GFR when using IDMS-Traceable Standardized Serum Creatinine lab values.

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