Prediction of Plasma Drug Concentration Profiles and Pharmacokinetic Parameters of Nifedipine Commercial Tablets using the Convolution Method

 

Hamzah Maswadeh¹*, Ahmed A. H. Abdellatif^1,2, Mohammed A. Amin^1,2, Aiman Y. Alwadi⁴, Mohamed A. Ibrahim^2,3

¹Department of Pharmaceutics, College of Pharmacy, Qassim University, Qassim, 51452,

 Kingdom of Saudi Arabia.

²Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Al-Azhar University,

 Assiut 71524, Egypt.

³Department of Pharmaceutics, College of Pharmacy, King Saud University, Saudi Arabia.

⁴Department of Pharmacy Practice, College of Pharmacy, Alfaisal University, Riyadh, Saudi Arabia.

 

ABSTRACT:

The aim of this study was to predict the blood/plasma drug concentration profiles for five brand of nifedipine present on the Saudi Arabia market by using the numerical convolution method and to estimate the pharmacokinetic parameters (^Cmax^{, T}max^{, K}a^{, K and V}d) by the application of the residual method to the predicted plasma drug concentration profiles. Results showed that the higher ^Cmax was 118.95ng/ml for brand A2 and the lower ^Cmax was 72.29ng/ml for brand A3. The Tmax was ranged from 2.3 hr to 4.9 hr for brands A2 and A3 respectively. The total area under plasma drug concentration curve ⁽AUCinf.⁾ was in lower value equal to 585.59 ng x hr/ml for brand A2 and the higher value was for brand A5 equal to 743.52ng x hr/ml. The volume of distribution was also increased from 52.5 L for free nifidipine to 72 L for brand A1. The predicted first order elimination rate constant was decreased from 0.34 hr^-1 for free nifedipine to 0.17 hr^-1 for brand A3. The half-life of nifedapine was increased from 2 hours for free drug to 3.93 hours for brand A3. From this study it can be concluded that brands present in the market that shows similarity in accordance to the Dissimilarity factor f1 are not always guaranty that they will be bioequivalent in vivo and vice versa. Also, this study indicates that the method of convolution is a useful tool for prediction of bioequivalence of different brands present on the market.

 

 

 

INTRODUCTION:

Nifedipine is a calcium channel blocking agent [Dimethyl-2,6-methyl-4-)2-nitrophenyl)-1,               4-

dihydropyridine-3, 5-dicarboxylate] class II in the Biopharmaceutics Classification System (BCS) with limited absorption from the gastrointestinal tract due to its poor solubility in water. Nifedipine is highly recommended in the management of angina pectoris and systemic hypertension due to better tolerance by patients^1,2,3,4,5.

 

Previous studies reported that extended-release dosage forms of nifedipine showed less side effects from immediate release dosage forms by reducing the appearance of steep rises in plasma concentration of the drug that increase heart rate in case of immediate release formulations^6,7.

 

The physical quality and the dissolution kinetics of commercially available extended-release dosage forms of nifedipine were extensively investigated. Previous studies based on dissolution profiles comparison of commercially available brands of nifedipine in different countries showed that in Belgian and India the majority of extended-release formulations of nifedipine present on the market were not similar while other studies showed that some formulations are  similar and other are not similar such as in Russia and Nigeria^8,9,10. However, all previous studies were in agreement that patients are not advised to shift from one brand to another without physician consultation^11,12,13,14.

 

Previous in vivo studies reported that the pharmacokinetic parameters obtained from the oral administration of extended-release formulation with different strength of nifidepine were also not bioequivalent and showed high variation in ^Cmax^{, T}max and AUC^15,16. It is important to note that there is no study for the prediction of pharmacokinetic parameters of commercially available extended-release formulations of nifidapine from dissolution data by using the convolution method. The convolution method is a simulation method used to predict the blood/plasma concentration profiles by combining percent absorbed data obtained from dissolution profile with reported pharmacokinetic (PK) parameters of a test drug such as elimination and distribution^17,18,19.

 

The aim of this study was to predict the blood/plasma drug concentration profiles for five commercial brand of nifedipine by using the method of convolution and to estimate the pharmacokinetic parameters ^(Cmax, ^Tmax, ^Ka, ^K and ^Vd⁾ by the application of the residual method to        the predicted plasma drug concentration profiles. The total area under plasma drug concentration curve ^(AUCinf.⁾ for all products was also calculated using the trapezoidal rule. The in vitro dissolution kinetics for all products was also investigated by using the first-order, the zero-order, the Hixson-Crowell and the Higuchi equation^{20,21,22,23,24,25}.

 

EXPERIMENTAL:    

MATERIALS:

Five brands of nifedipine ER were purchased from the Saudi Arabia market. Nifedipine ≥98% (HPLC), acetonitrile HPLC grade were obtained from Sigma – Aldrich, Merck KGaA, Darmstadt, Germany.

 

METHODS:

In vitro dissolution study of nifedipine ER brands present on the Saudi Arabia market was conducted using a UDT-804 Logan dissolution tester (Logan, USP). Twelve tablets from each brand were used. The dissolution media was 900ml phosphate buffer pH 6.8 at a paddle speed of 50rpm and temperature at 37±0.5°C. Samples were collected for 12 h. The amount of drug released in each sample was determined using analytical HPLC system consisted of an Alliance 1525 separation module, automatic HPLC system equipped with UV/Vis detector 2489 (Waters, USA). The separation was achieved on column Agilent Prep-C18 Scalar, 4.6 x 250 mm, 10µm and the mobile phase was composed of 70:30 v/v of acetonitrile and water, the volume of injection was  20ul and the flow rate was 1.5ml/min. The UV/ Vis detector was set at 350nm.

 

RESULTS AND DISCUSSION:

A dissolution experiment was conducted for five commercial brands of nifedipine present on the Saudi Arabia market. As shown in table 1 and figure 1 the correlation coefficient r² values after the application of the zero-order equation for the five brands (A1, A2, A3, A4 and A5) was lower than r² values obtained after the application of the first order equation (Figure 2).

 

Fig. 1: % dissolved versus time (hr) in accordance to the zero- order equation for A1 (◊), A2 (□), A3 (∆), A4 (x) and A5 (ж).

 

Table 1: Dissolution rate constant and r2 for zero-order, first-order, Higuchi and Hixson-Crowell models.

Brand	Zero-Order dissolution rate constant (hr-1)	First-Order dissolution rate constant (hr-1)	Higuchi dissolution rate constant (hr-1)	Hixson-Crowell dissolution rate constant (hr-1)
A1	34.82 r2= 0.821	4.64 r2= 0.994	6.45 r2= 0.936	0.500 r2= 0.953
A2	12.99 r2= 0.833	5.12 r2= 0.992	28.14 r2= 0.935	0.9095 r2= 0.982
A3	18.51 r2= 0.908	4.71 r2= 0.998	12.39 r2= 0.980	0.484 r2= 0.983
A4	23.69 r2= 0.868	4.86 r2= 0.990	8.17 r2= 0.961	0.791 r2= 0.943
A5	18.68 r2= 0.850	4.94 r2= 0.990	15.17 r2= 0.937	0.931 r2= 0.942

 

Fig. 2: Log % remaining versus time (hr) in accordance to the first-order equation for A1 (◊), A2 (□), A3 (∆), A4 (x) and A5 (ж).

 

To study the mechanism of dissolution profile for the five brands, the Higuchi model and Hixson-Crowell equation were used. Figure 3 and Table 1 showed that only A4 product followed Higuchi equation with r² equal to 0.961, which indicate that the mechanism of drug release was diffusion controlled for brand A4. The application of Hixson–Crowell equation to the dissolution data showed that the drug release mechanism for brands A1, A2, A3 and A5 was dissolution controlled with r2 values equal to 0.953, 0.982, 0.983, respectively (Figure 4)

 

Fig. 3: Plot for the dissolution data in accordance to Higuchi equation for A1 (◊), A2 (□), A3 (∆), A4 (x) and A5 (ж).

 

Fig. 4: Plot for the dissolution data in accordance to Hixson- Crowell equation for A1 (◊), A2 (□), A3 (∆), A4 (x) and A5 (ж).

To test the in vitro similarity of the five brands, the dissolution profile comparison was done by calculating the Dissimilarity factor f1 for all possible brand peers as shown in Figure 5. The f1 values (Figure 5) showed that A1 – A4, A3 – A4, A3 – A5 and A4 – A5 were similar with f1 values equal to 9.8, 9.7, 9.1 and 5.7 respectively. The results obtained from the in vitro similarity factor for the commercial brand tested in this study does not necessary mean that they are also similar in vivo (bioequivalent).

 

Fig. 5: Dissimilarity factor f1 for all nifedipine brands used in this study.

 

For many reasons, sometimes patients can’t find their prescribed or used medication in the community or hospital pharmacy. In this case physician’s and clinical pharmacists facing a challenge for fast and effective replacement of medication with another commercial brand present in the market taking into account that the alternative brand must be bioequivalent with the medication used to achieve the same therapeutic response without any side effect or toxicity. Due to this fact, studies for the prediction of plasma drug concentration curve and the prediction of the expected values of bioavailability parameters ^(Cmax, ^Tmax and AUCTotal⁾ from dissolution data for commercially available dosage forms can offer a fast solution for the possible most suitable brand in the market that can replace the medication used to achieve the same therapeutic response with minimum risk of side effect. The final decision for continuing the administration of the alternative medication or not will be taken after drug monitoring in plasma and physician observation.

 

To test if the five brands used in this study are bioequivalent or non-bioequivalant, we used the convolution method to predict the blood/plasma concentration profiles by combining percent absorbed data obtained from dissolution profile with reported pharmacokinetic (PK) parameters of free nifedipine such as elimination and distribution.

 

The pharmacokinetic parameters used for nifedipine in this study were the half-life of 2 hours, the volume of distribution of 52.5 L (for a patient weighing 70 Kg) and oral bioavailability of 0.5 as reported in the bibliography^26,27,28. Based on the dissolution data the % dissolved was converted to % absorbed and the amount absorbed was converted to plasma drug concentration (ng/ml) by using the following equation:

 

Concentration (ng/ml) = Amount × bioavailability × 1000/volume of distribution                                     (1)

 

The predicted plasma drug concentration for the five brands of nifedipine ER tablets were calculated and plotted in figure 6. The pharmacokinetic parameters such ^{as C}max^{, T}max^{, K, K}a ^{and V}d ^{for nifedipine for each brand} were calculated as shown in table 2 by using the residual method according to the following equation^17,19:

 

Cp= A (e-^Kt – e^-Kat)                                                     (2)

 

In which:

K: is the first order elimination rate constant (hr^-1) ^Ka: is the first order absorption rate constant (hr^-1)

A: is the intercept for both phases equal to F x Dose/Vd (K_a – K)

The area under plasma drug concentration curve

(AUCTotal) for all brands was also calculated by using the  trapezoidal rule:

[AUCTotal^] = area 1 + area 2 +-----+ area n + ^Cn/     (3)

 

In which:

^Cn: is the last concentration in ng/ml and

K: is the first order elimination rate constant (hr^-1)

 

Fig. 6: Predicted plasma drug concentration curve versus time (hr) for nifedipine brands present on the Saudi market. A1 (◊), A2 (□), A3 (∆), A4 (o) and A5 (ж).

 

Table 2 showed a variation in the predicted ^{pharmacokinetic parameters C}max^{, T}max ^{and [AUC}Total^{]. More specific, the higher C}max ^{was 118.95 ng/ml for brand A2 and the lower C}max ^{was 72.29 ng/ml for brand A3. The T}max ^{was ranged from 2.3 hr to 4.9 hr. The total area under plasma drug concentration curve [AUC}Total^] was in lower value equal to 585.59 ng x hr/ml for A2 and the higher value was for A5 equal to 743.52 ng x hr/ml. The volume of distribution was also increased from 52.5 L for free nifidipine to 72 L for brand A1. The predicted first order elimination rate constant was decreased from 0.34 hr^-1 for free nifedipine to 0.17 hr^-1 for brand A3 as shown in table 2.

 

The decrease in the first order elimination rate constant produces an increase in the half-life of nifedapine. The half-life of nifedapine was increased from 2 hours for free drug to 3.93 hours for brand A3. This finding is in agreement with previous studies mentioned that extended release dosage forms increase the half-life of nifedipine^6,11,13

 

To test if the five brands are predicted to be similar or non-similar in vivo, the bioequivalence test was performed for all possible brand combinations. The bioequivalence test is based on a comparison of ratios where the ratio of reference product to test product for ^{the three parameters of bioavailability (C}max^{, T}max ^{and AUC}Total^{) does not differ by less than 8/10 (lower limit} 0.8) and more than 10/8 (upper limit 1.25). If the three bioavailability parameters are in the range of 0.8 to 1.25, the two brands are considered bioequivalent.

 

Table 3 shows the predicted upper and lower limit of the ratio for all brands used in this study. From the results shown in table 3 it is evident that only three out of ten peers of commercial brand are bioequivalent (A1-A4, ^{A1-A5 and A4-A5) with C}max^{, T}max ^{and AUC}Total ^within the range of 0.8 – 1.25. Other brand peers such as A3-A4 ^{and A3-A5 were similar in vitro with f}1 ^{equal to 9.7 and} 9.1 respectively, while the in vivo bioequivalence test ^{showed that they are non-bioequivalent with C}max ^{and T}max ^{out of the upper and lower range of 1.25 to 0.8.} From the other hand, brands such as A1-A5 showed non- ^{similar in vitro with f}1 ^{value equal to 13.6, showed that} they are bioequivalent in the in vivo prediction test.

Table 2: Predicted pharmacokinetic parameters for all brands of nifedepine A1, A2, A3, A4 and A5.

Product	Cmax (ng/ml)	Tmax (hr)	K (hr-1)	Elim. Half- life (hr)	Ka (hr-1)	Abs. half-life (hr)	AUC (ng.hr/ml)	Vd (L)
A1	81.42	2.70	0.19	3.64	0.6	1.15	632.66	72.0
A 2	118.95	2.34	0.29	2.34	0.59	1.17	585.59	42.3
A 3	72.29	4.90	0.17	3.93	0.44	1.56	739.86	70.7
A 4	80.00	3.08	0.19	3.53	0.51	1.35	702.44	68.5
A 5	99.00	3.37	0.18	3.85	0.45	1.52	743.52	54.8

Table 3: The lower and the upper limits obtained from the ^{bioequivalence test for the bioavailability parameters (C}max^{, T}max ^{and AUC}Total^{) for all brands peers of nifedipine}

Brands	The lower and upper limits for
	Cmax	Tmax	AUCTotal
A1 - A2	68.4 - 146.0	86.6 -115.3	92.0 - 108.0
A1 - A3	88.7 - 112.6	55.1 - 181.4	85.5 - 116.9
A1 - A4	98.2 - 101.7	87.6 - 114.0	90.0 - 111.0
A1 - A5	82.2 - 121.5	80.1 - 124.8	85.0 - 117.5
A2 - A3	60.7 - 164.5	47.7 - 209.4	79.1 - 126.3
A2 - A4	67.2 - 148.6	75.9 - 131.6	83.3 - 119.9
A2 - A5	83.2 - 120.1	69.4 - 144.0	78.7 - 126.9
A3 - A4	90.3 - 110.6	62.8 - 159.0	94.9 - 105.3
A3 - A5	73.0 - 136.9	68.7 - 145.4	99.5 - 100.4
A4 - A5	80.8 - 123.7	91.3 - 109.4	94.4 - 105.8

 

As shown in table 3, the main pharmacokinetic parameter that was out of the range of 0.8 to 1.25 for 6 brands peers and was responsible alone or with other pharmacokinetic parameters for non-bioequivalence was ^{the T}max^{, the second parameter was C}max ^{for four brands peers and finally, AUC}Total ^{for two brands peers out of} 10.

 

From this study it can be concluded that brands present in the market that shows similarity in accordance to the ^{dissimilarity factor f}1 ^{are not always guaranty that they} will be bioequivalent in vivo and vice versa. Also, this study indicates that the method of convolution is a useful tool for prediction of bioequivalence of different brands present on the market. Prediction of pharmacokinetic parameters helps physicians and clinical pharmacists to decide which brand is suitable to replace another brand with minimum expected side effect and maximum therapeutic response; simultaneously they can conduct drug monitoring in plasma to estimate the real experimental values of the pharmacokinetic parameters for final decision.

 

CONFLICT OF INTEREST:

The authors do not have any conflict of interest

 

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Accepted on 26.03.2021           © RJPT All right reserved

Research J. Pharm. and Tech 2021; 14(10):5380-5384.