The retrospective study analyzed PK characteristics in patients receiving both drugs. From January 1, 2024, to March 31, 2024, the patients who were prescribed both potassium chloride sustained-release tablets and potassium citrate granules were enrolled in Fuwai Yunnan Hospital, Kunming, China from Hospital Information System. The inclusion criteria, according to the enrollment criteria: (1) adult patients (>18 years old); (2) emergency patients with cardiovascular diseases (e.g., angina, arrhythmia, and heart failure); (3) patients who were co-administered potassium chloride sustained-release tablets and potassium citrate granules. The exclusion criteria were patients: (1) on diuretics in the emergency setting; (2) with communication problems or other problems such as visual or hearing impairment. The potassium citrate granules was purchased from Changchun Beihua Pharmaceutical Co., Ltd. (Changchun, Jilin, China)(0.5 g, Approval Number: H22024249). The potassium chloride extended-release tablets was purchased from Shanghai haihong Group Chaohu C-Dragon Pharmaceutical Co., Ltd. (Shanghai, China)(2 g, Approval Number: H34021120). Physicians prescribed three dosing regimens: 1-dose (potassium chloride extended-release tablets 0.5245 g + potassium citrate granules 0.5589 g), 2-dose (1.049 g + 1.1178 g), and 3-dose (1.5735 g + 1.6767 g). Each dose was administered at 0.5-hour intervals, with a maximum of three doses. The study protocol was approved by the Ethics Committee of Fuwai Yunnan Cardiovascular Hospital, Kunming, China (No.2024-046-01). The human samples used in this study were acquired from a by- product of routine care.

Plasma potassium parameters were calculated using the WinNonlin 7.0 Software (Pharsight Corporation, Mountain View, CA, USA) via non-compartmental modeling. Linear regression methods were employed to analyze the relationship between the limited areas under the plasma curve (AUC_limit) and co-administered dose. The experimental data were expressed as mean ± standard deviation. Statistical analyses were using the GraphPad Prism 6 software (San Diego, CA, USA).

According to the criteria, 330 emergency patients who were prescribed both potassium chloride sustained-release tablets and potassium citrate granules were enrolled. The characteristics of the 330 patients are presented in Table 1. Due to subtle physiological adjustments in muscle mass, hormones, and kidney function, women's serum potassium levels are on average approximately 0.1–0.2 mmol/L lower than men's. Table 1 presents gender-specific subgroup data, though no statistically significant differences were observed in pre-co-administered values. Post-co-administered values is statistically significant differences(P < 0.05).

Plasma potassium was elevated in emergency patients using co-administration potassium supplements (potassium chloride extended-release tablets and potassium citrate granules). The mean concentration–time curves of potassium concentration in the plasma of emergency patients were determined, as shown in Figure 1A. The patient's plasma potassium concentration before potassium supplementation (1-dose administration group, 2-dose administration group, and 3-dose administration group) was 3.70 ± 0.24 mmol/L, 3.54 ± 0.29 mmol/L, and 3.36 ± 0.26 mmol/L. The 12-hour time point showed the largest difference in the increase in plasma potassium concentration, which is 0.005 ± 0.56 mmol/L, 0.45 ± 0.46 mmol/L, and 0.86 ± 0.51 mmol/L, respectively (Figure 1B) (P < 0.0001).

The pharmacokinetic parameters for plasma potassium concentrations are presented in Table 2. The following parameters were calculated by WinNonlin Software. Each dose elevated plasma potassium by 0.31 ± 0.05 mmol/L. The AUC_limit were: 30.37 mmol·h/L, 106.89 mmol·h/L, and 141.74 mmol·h/L. Linear regression of co-administered dose and AUC were showed as follows:

AUC=55.69 × times of dose-18.37 (R² = 0.9554).

where times of dose including 1, 2, or 3 represent 1-dose administration group(8.7583 mol), 2-dose administration group(17.5166 mol), or 3-dose administration group(26.2749 mol).

Due to the widespread use of diuretics, hypokalemia often occurs in acute patients with cardiovascular disease. We suggest that patients with cardiovascular disease who use diuretics, especially potassium-excreting diuretics, could use plus supplements on a daily basis. Studies have shown that a low-potassium diet activates the potassium-sensing signaling pathway in the renal distal convoluted tubule, increasing the activity of the sodium-chloride cotransporter and sodium retention, thereby elevating blood pressure and enhancing salt sensitivity (7, 8). In contrast, increasing potassium intake could lower blood pressure by enhancing AngII-stimulated aldosterone secretion (without affecting cardiovascular responses), primarily through a diuretic mechanism (9). Hypertensive patients exhibit greater sensitivity to increased potassium intake compared to normotensive individuals, with particularly pronounced benefits for those on a high-salt diet (10). A high-potassium diet effectively reduces blood pressure in individuals with prehypertension and hypertensionand reverses endothelial dysfunction induced by high sodium intake, mitigating vascular damage (11). Additionally, dietary potassium not only improves blood pressure (12, 13). but also enhances glucose tolerance and insulin resistance (14). These studies confirm the multifaceted cardiovascular and metabolic benefits of dietary potassium. This might reduce the risk of developing serious cardiovascular disease.

The conventional opinion is that fluctuations in plasma potassium caused by oral potassium-supplementing preparations are difficult to detect, and that intravenous administration without an absorptive phase is easier for raising plasma potassium. Oral extended-release preparations could delay potassium release in order to minimize gastrointestinal irritation (3). In this study, we found a linear relationship between the administered dose and plasma AUC in patients with cardiovascular emergencies. This provides an evidence-based basis for potassium supplementation in these patients. To rapidly replenish a patient's plasma potassium, physicians use the strategy of fast-absorbing granules preparations (potassium citrate granules) and slow-absorbing extended-release preparations. This combination achieves rapid, prolonged potassium supplementation.

The T_max of the combination was prolonged to 4–6 h compared to the 1 h T_max of granules KCl in the literature (4, 5). Patient's plasma potassium rose rapidly over a 2 h period and K_a averaged 0.35. Drug absorption was at 2–6 h for 3-dose administration due to the extended-release dosage form. 3-dose administration approximated an equilibrium of absorption and elimination at 6–12 h, with Ka = Ke = 0.10. It can be hypothesized that the Ka of KCl extended-release tablets alone might be 0.10 with a t1/2 of 6.93 h. Based on this, if the goal is to maintain target plasma potassium levels, the recommended dosing interval should approximate the apparent half-life of the extended-release component multiplied by the number of doses administered. The number of administrations can be calculated based on the patient's pre-administration plasma potassium level. Therefore, (1) 1-dose administration: the need to maintain attained plasma potassium concentrations suggests that a second dose be given after 6.93 h. (2) 2-dose administration: it is recommended to be re-dosed after 13.86 h to maintain the standardized. (3) 3-dose administration: it is recommended to be re-dosed after 20.79 h to maintain the standardized. Further studies would be needed to confirm the K_a results for KCl extended-release tablets.

Among our 330 patients, 8 cases (2.4%) developed transient serum potassium elevation >5.0 mmol/L after administration, with the highest value being 5.3 mmol/L. All were asymptomatic, received no specific treatment, and returned to normal levels during subsequent monitoring. This relatively low incidence of hyperkalemia may be attributed to the following factors: (1) The extended-release formulation avoided rapid spikes in serum potassium; (2) The combination of liquid and solid formulations provided a relatively stable serum potassium profile; (3) Close monitoring of emergency patients.

There are some limitations of this study. Patients using diuretics were not selected during the study, reducing the interference of the elimination phase. Further studies are needed to investigate the effect of diuretics on potassium-supplementing medications in real-world.