Abstract
Ciprofol (also known as HSK3486) is a promising intravenous anesthetic candidate derived from propofol and independently developed by Haisco Pharmaceutical Group Co., Ltd. (Chengdu, China). Compared with propofol, ciprofol has the potential to reduce the dose required and the associated risks. Ciprofol is extensively metabolized in vivo, and its interaction with other concurrently administered drugs during clinical application is worthy of attention. Therefore, an open‐label, two‐stage sequential study was performed in healthy subjects who received either a single administration of ciprofol injection or ciprofol injection after oral administration of sodium divalproex. The aim of the study was to evaluate the effects of sodium divalproex on ciprofol with respect to pharmacokinetics, pharmacodynamics, and safety, thus providing a basis for the rational clinical use of ciprofol and sodium divalproex.
Study Highlights.
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Ciprofol is a promising intravenous anesthetic candidate derived from propofol and is extensively metabolized after administration. Compared with propofol, ciprofol shows faster onset of action, higher target selectivity, and higher activity. The dispensatory of propofol suggests that the plasma concentration may be increased after combination with sodium divalproex. There are similarities between ciprofol and propofol in their chemical structure and metabolic pathway in vivo.
WHAT QUESTION DID THIS STUDY ADDRESS?
This study was designed to investigate the effect of sodium divalproex on ciprofol in terms of pharmacokinetics (PKs), pharmacodynamics (PDs), and safety in healthy subjects, thus providing a basis for the rational clinical use of ciprofol and sodium divalproex.
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
In Chinese healthy subjects, the combination of sodium divalproex and ciprofol has no significant effect on the PK parameters of ciprofol, indicating no drug interaction between them. Moreover, there was no significant effect on the PDs or safety of ciprofol either before or after combination with sodium divalproex.
HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
This study provides a basis for rational clinical use of ciprofol and sodium divalproex and will encourage approval of ciprofol for more indications.
INTRODUCTION
Propofol is one of the most widely used intravenous anesthetics because of its rapid induction and recovery. It is widely used in the induction and maintenance of general anesthesia for surgery as well as for outpatient surgery. However, the shortcomings of propofol are also becoming increasingly prominent; these mainly include injection pain, decreases in diastolic blood pressure and mean arterial blood pressure, respiratory depression, and lipid metabolism disorder. 1 , 2 , 3 Attempts have been made to alleviate the pain of propofol injection, which has generally been believed to be related to the aqueous concentration in the propofol emulsion formulation. 1 , 4 However, limited success has been achieved.
Ciprofol (also known as HSK3486) is a novel 2,6‐disubstituted phenol derivative based on propofol. It was independently developed by Haisco Pharmaceutical Group Co., Ltd. (Chengdu, China) and first reported in 2017. 5 , 6 Ciprofol may be safer with respect to respiratory function and may have a lower risk of injection pain than propofol because of the lower water content in the emulsion. 5 Therefore, ciprofol is a promising intravenous anesthetic candidate. Ciprofol has been approved by the China National Medical Products Administration (NMPA) for various indications, including sedation during gastrointestinal endoscopy and general anesthesia. 7 Clinical studies of ciprofol have been conducted in various procedures and settings, including gastroscopy and colonoscopy, 8 fiberoptic bronchoscopy, 9 , 10 general anesthesia for elective surgery, 11 and mechanical ventilation in the intensive care unit. 12 Ciprofol was further shown to be comparable in efficacy to propofol with fewer adverse events (AEs) in gynecologic surgery, in major non‐cardiac surgery in patients of advanced age, and for management of agitation and delirium in the intensive care unit. 13 , 14 , 15
Ciprofol is extensively metabolized after administration; this primarily occurs in the liver through phase I cytochrome P450 (CYP) 2B6 and phase II glucuronosyltransferase 1A9 (UGT1A9). 7 , 16 A mass balance and biotransformation study showed that the major metabolites in plasma were glucuronic acid‐M4 (~79.3% of the total plasma radiation exposure) and that those in urine were M4 and M5‐1 (accounting for 51.6% and 19.3% of the dose, respectively) after a single intravenous dose of 0.4 mg/0.8 μCi/kg [14C] ciprofol. 17 By contrast, unchanged ciprofol accounted for only 3.97% of the total radiation exposure and was not detected in urine, which further demonstrated that the major metabolite was M4 and was mainly excreted via the kidneys (84.59%). 17
Due to potential drug–drug interactions, caution is warranted when concomitantly using ciprofol and sodium divalproex. Sodium divalproex is an anti‐epileptic drug that is also used for management of mania and prevention of migraine headaches. 18 Studies have shown that valproate sodium can increase the gene expressions of CYP (e.g., CYP1A1) and ATP binding cassette transporter G1 (ABCG1), which are related to fatty acid metabolism, and this may be one of the main causes of its hepatotoxicity. 19 The package insert for propofol suggests that the concomitant use of valproate and propofol may lead to increased blood levels of propofol, and the dose of propofol should be reduced when it is co‐administered with valproate. A possible explanation for the effect of divalproex on propofol exposure may be that divalproex inhibits propofol‐metabolizing enzymes. In vitro studies have shown that divalproex inhibits propofol‐metabolizing enzymes, such as CYP2C9 and UGT1A9. 20 , 21 Considering the similarities in the structure and metabolic pathway between ciprofol and propofol, this study was designed to investigate the effect of sodium divalproex on the pharmacokinetics (PK), pharmacodynamics (PD), and safety of ciprofol in healthy subjects. The study provides a basis for the rational clinical use of ciprofol and sodium divalproex.
METHODS
Ethics
Before its implementation, the study protocol (and its amendments) and informed consent (and its updates) were approved by the ethics committee of the Second Affiliated Hospital of Zhejiang University School of Medicine. The design, conduct, and reporting of this study were in accordance with the International Conference on Harmonization Good Clinical Practice (ICH‐GCP) guideline, the Good Clinical Practice (GCP) guideline, the current Helsinki Declaration, the relevant regulations of the China NMPA, and the opinions of the ethics committee.
Study population
Healthy men (body weight ≥ 50 kg) and women (body weight ≥ 45 kg and not pregnant or lactating) aged 18–45 years with a body mass index of 19–26 kg/m2 were recruited. Eligible subjects underwent health assessments according to specified evaluation items, including a physical examination, laboratory screening, 12‐lead electrocardiogram (ECG), and chest radiographs. Subjects were excluded if they had any present or past clinically significant medical condition, a history of drug abuse, a history of alcoholism, a history of anesthetic complications, a contraindication to deep sedation/general anesthesia, or an allergy to the investigational drugs (ciprofol and sodium divalproex). Subjects were also excluded if they were hypersensitive and/or had contraindications to the use of any substances in this study, including hypersensitivity to ciprofol and its excipients (soybean oil, glycerin, triglyceride, egg yolk lecithin, sodium oleate, and sodium hydroxide); hypersensitivity to sodium divalproex or contraindications listed in the product insert for sodium divalproex; hypersensitivity to other drugs, foods, or substances; or a clinically significant history of allergic reactions. Finally, subjects were excluded if they had participated in a clinical trial within 3 months, had used any drug within 14 days, had a positive urine nicotine screen, had donated or lost greater than or equal to 200 mL of blood within 30 days, or were unsuitable for arterial blood sampling (e.g., positive Allen test). All eligible subjects were informed of the procedures and methods of the study, voluntarily signed the informed consent form, and completed the study in strict accordance with the study protocol. Prior to withdrawal, the subjects were required to complete several end‐of‐study items, including laboratory screening, vital signs, 12‐lead ECG, laboratory examination, and urine pregnancy test (women only).
Study design
A single‐center, open‐label, two‐stage sequential study of healthy subjects was conducted to evaluate the effect of sodium divalproex on the PKs, PDs, and safety of ciprofol (NCT05181007) at the Clinical Pharmacology Center of the Second Affiliated Hospital of Zhejiang University School of Medicine. All procedures were performed at the research center under the supervision of the investigators. The study design and treatments are summarized in Figure 1. Briefly, the subjects received a single injection of ciprofol (Lot: 20211102; Haisco Pharmaceutical) on day 1 (stage I) at a dose of 0.4 mg/kg. After a 3‐day washout period, oral sodium divalproex extended‐release tablets (Depakote ER, Lot: 1151758; AbbVie) were administered multiple times from days 4 to 8 (stage II) at a dosage of 1000 mg/day according to a previous report. 22 On day 8, ciprofol was again injected as a single dose 2 h after sodium divalproex administration. After ciprofol injection (the initial administration of ciprofol was defined as “0 min”), blood samples for PK analysis were collected in EDTA‐K2 anticoagulant tubes (Becton, Dickinson, and Company) at pre‐set timepoints; the samples consisted of 3 mL of arterial blood (within −30 min, 1 min, 2 min, 4 min, 8 min, 15 min, 30 min, and 1 h) and 3 mL of venous blood (2, 3, 4, 6, 8, 12, and 24 h). The window for blood collection was ±6 s within 1 min, ±10 s for 2–4 min, ±1 min for 8 min–1 h, and ± 10 min for 2–24 h. The plasma was then separated from the whole blood by centrifugation (1700 g, 10 min at 2–8°C). The separated plasma samples were transferred to a freezer at −90 to −60°C. The concentration of ciprofol in plasma samples was determined using liquid chromatography with tandem mass spectrometry (Shanghai Xihua Scientific Co., Ltd.). The analytical method validation and analytical procedures met the requirements of the guidelines issued by the NMPA and the standard operating procedures of the company.
FIGURE 1.
Schedules of study design and treatment. Ciprofol was administered as a single dose of 0.4 mg/kg infused intravenously for 1 min before meals in the morning of the first day. For sodium divalproex administration, the subjects took 1000 mg of sodium divalproex orally once a day after meals from days 4 to 7 (five times total) after a washout period of 3 days. On the morning of day 8, ciprofol was administered again as a single dose of 0.4 mg/kg infused intravenously for 1 min before meals and 2 h after the administration of sodium divalproex. PD, pharmacodynamic; PK, pharmacokinetic.
For PD analysis, the Modified Observer's Assessment of Alertness and Sedation (MOAA/S) scale (Table S1) and the bispectral index (BIS) were used to evaluate the depth of anesthesia. Specifically, the MOAA/S score was assessed once within 5 min before ciprofol administration, every 1 min ± 10 s for the first 5 min after administration, and then every 2 min ± 30 s until the subjects had fully recovered. The investigators could increase the frequency of assessment as necessary. The time to full recovery was defined as the duration from the end of dosing to the first achieved MOAA/S score of grade 5 among three consecutive evaluations of an MOAA/S score of grade 5. The BIS time variations were recorded within 5 min before and at the beginning of ciprofol administration (0 min), every minute within the first 30 min after administration, and then at 45 min ± 2 min and 60 min ± 2 min. The investigators could increase the frequency of assessment as needed.
Safety monitoring
Throughout the study, the safety of the investigational products was evaluated using the AE records (from acquisition of informed consent to completion of the safety follow‐up), laboratory evaluations, vital signs, physical examination, 12‐lead ECG, and other indicators (including blood pressure, respiration, and oxygen saturation).
Statistical analysis
The data were statistically analyzed using SAS software, version 9.4 or later (SAS Institute). The PK parameters were estimated using the noncompartmental model of WinNonlin software, version 7.0 or later (Pharsight Corporation).
The plasma concentrations were categorized according to the study stage and collection time, and the descriptive statistics were generated for the blood drug concentrations at different study stages. These data are expressed as number (n), below quantifiable limit, arithmetic mean (mean), standard deviation (SD), coefficient of variation (CV%), minimum, median, maximum, geometric mean (geo mean), and geometric coefficient of variation (geo CV%). Descriptive statistical analysis of PK parameters was performed by study stage, and the data are presented as n, mean, SD, CV%, median, minimum, maximum, geo mean, and geo CV%. The geometric mean ratio (GMR) of the parameters (area under the concentration‐time curve from time of administration up to the time of the last quantifiable concentration [AUC0–last], maximum plasma concentration [C max], and AUC from zero to infinity [AUC0–inf]) in patients who received ciprofol and those who received ciprofol in combination with sodium divalproex was used for drug–drug interaction assessment. The 90% confidence interval of the GMR was within 80.00%–125.00%, which was considered to indicate no effect on the PK parameters between the combination of drugs (ciprofol and sodium divalproex) and ciprofol alone. The Wilcoxon signed rank‐sum test was used for statistical analysis of terminal half‐life (t 1/2) and time to C max (T max) in both stages.
For PD analysis, descriptive statistics were performed using the BIS and MOAA/S score at each timepoint. BIS indicators included the BIS, BISpeak (minimum BIS), T BISpeak (time of peak BIS), and BIS AUC0–last. The statistics of BIS statistics included n, number of missing (n miss), mean, SD, median, minimum, maximum, CV%, geo mean, and geo CV%.
Safety analysis was based on the safety set, defined as subjects who received at least one dose and underwent at least one safety assessment. Treatment‐emergent AEs (TEAEs) were defined as AEs that were related or unrelated to the investigational products after administration; the appearance of a new disease or worsening of a pre‐existing condition after administration was also considered a TEAE. The frequency and percentage of AEs were then summarized and analyzed: all TEAEs, investigational product‐related TEAEs, serious AEs, investigational product‐related serious AEs, withdrawal‐related TEAEs, and the investigational product‐related TEAE leading to withdrawal.
RESULTS
Demographics and baseline characteristics
The study subjects comprised 17 (85%) men and 3 (15%) women, and their demographic data are shown in Table 1. The subjects' mean age was 27.8 years (range, 22–38 years), mean weight was 64.23 kg (range, 49.7–76.2 kg), mean height was 169.04 cm (range, 155.2–178.9 cm), and mean body mass index was 22.46 kg/m2 (range, 19.7–25.2 kg/m2). Two of the 20 enrolled subjects were withdrawn from the study because of extravasation of the intravenous dose. Two of the subjects had a medical history or current illness, and the investigator were determined that they met the inclusion criteria, but did not meet the exclusion criteria. No subjects had a history of surgery or drug abuse, and all had negative results for the alcohol breath test, urine nicotine test, and Allen test. The chest radiograph findings were normal in all subjects with the exception of one who had abnormal findings of no clinical significance. All women's pregnancy test results were negative prior to administration of the drugs in both stages of the study.
TABLE 1.
The demographic data and baseline characteristics of enrolled subjects (n = 20).
| Parameter | Mean (SD) or n (%) |
|---|---|
| Sex | |
| Male | 17 (85%) |
| Female | 3 (15%) |
| Age, years | 27.8 (4.89) |
| Weight, kg | 64.23 (6.785) |
| Height, cm | 169.04 (6.573) |
| BMI, kg/m2 | 22.46 (1.954) |
| Ethnicity | |
| Han | 19 (95%) |
| Other | 1 (5%) |
Abbreviations: BMI, body mass index; n, number.
Analysis of ciprofol plasma concentration
The plasma concentration–time curves are shown in Figure 2. After ciprofol administration, the plasma concentration of ciprofol was similar at each scheduled timepoint between the first stage (ciprofol) and the second stage (combination of sodium divalproex and ciprofol; Figure 2). The main PK parameters of the subjects in the two stages are shown in Table 2 and Figure S1. The T max of stage I and stage II was 0.0169 and 0.0171 h, respectively; the geo mean of C max was 6500 and 5860 ng/mL; the geo mean of AUC0–last was 336 and 299 h ng/mL; the geo mean of AUC0–inf was 363 and 320 h ng/mL; the t 1/2 was 3.13 ± 1.43 and 2.39 ± 0.837 h; the clearance was 70.1 ± 10.0 and 79.4 ± 10.7 L/h; and the volume of distribution was 305 ± 122 and 268 ± 83.4 L, respectively.
FIGURE 2.
Plasma concentration–time curves of ciprofol in the two stages.
TABLE 2.
Statistical analysis of major PK parameters.
| PK parameters | Statistics | Stage I (n = 18) | Stage II (n = 18) |
|---|---|---|---|
| C max (ng/mL) | n (n miss) | 18 (0) | 18 (0) |
| Mean (SD) | 6580 (1070) | 5890 (634) | |
| Median (minimum, maximum) | 6520 (5150, 8610) | 5920 (4640, 6850) | |
| CV, % | 16.3 | 10.8 | |
| Geo mean (geo CV, %) | 6500 (16.1) | 5860 (11.1) | |
| AUC0–last (h ng/mL) | n (n miss) | 18 (0) | 18 (0) |
| Mean (SD) | 366 (53.1) | 323 (47.9) | |
| Median (minimum, maximum) | 360 (271, 480) | 326 (218, 390) | |
| CV, % | 14.5 | 14.8 | |
| Geo mean (geo CV, %) | 363 (14.6) | 320 (15.6) | |
| t 1/2 (h) | n (n miss) | 18 (0) | 18 (0) |
| Mean (SD) | 3.13 (1.43) | 2.39 (0.837) | |
| Median (minimum, maximum) | 2.34 (1.51, 5.97) | 2.18 (1.37, 4.04) | |
| CV, % | 45.8 | 35 | |
| Geo mean (geo CV, %) | 2.84 (47.9) | 2.27 (33.3) | |
| T max (h) | n (n miss) | 18 (0) | 18 (0) |
| Mean (SD) | 0.0171 (0.000257) | 0.0171 (0.000303) | |
| Median (minimum, maximum) | 0.0169 (0.0167, 0.0175) | 0.0171 (0.0167, 0.0175) | |
| CV, % | 1.5 | 1.78 | |
| Geo mean (geo CV, %) | 0.0171 (1.5) | 0.0171 (1.78) | |
| CL (L/h) | n (n miss) | 18 (0) | 18 (0) |
| Mean (SD) | 70.1 (10.0) | 79.4 (10.7) | |
| Median (minimum, maximum) | 72.7 (53.7, 86.9) | 78.9 (65.1, 102) | |
| CV, % | 14.3 | 13.4 | |
| Geo mean (geo CV, %) | 69.4 (14.7) | 78.8 (13) | |
| V z (L) | n (nmiss) | 18 (0) | 18 (0) |
| Mean (SD) | 305 (122) | 268 (83.4) | |
| Median (minimum, maximum) | 258 (177, 588) | 248 (186, 481) | |
| CV, % | 40 | 31.1 | |
| Geo mean (geo CV, %) | 284 (39.5) | 258 (28) | |
| K el (1/h) | n (n miss) | 18 (0) | 18 (0) |
| Mean (SD) | 0.2680 (0.1118) | 0.3197 (0.0965) | |
| Median (minimum, maximum) | 0.2957 (0.1161, 0.4576) | 0.3184 (0.1716, 0.5073) | |
| CV, % | 41.7147 | 30.175 | |
| Geo mean (geo CV, %) | 0.2444 (47.912) | 0.305 (33.3393) | |
| AUC_%Extrap (%) | n (n miss) | 18 (0) | 18 (0) |
| Mean (SD) | 7.32 (2.82) | 6.62 (1.76) | |
| Median (minimum, maximum) | 6.00 (3.88, 11.3) | 6.48 (4.01, 10.6) | |
| CV, % | 38.4 | 26.6 | |
| Geo mean (geo CV, %) | 6.82 (40.5) | 6.41 (26.3) |
Abbreviations: AUC0‐last, area under the concentration‐time curve from time of administration up to the time of the last quantifiable concentration; CL, clearance; C max, maximum plasma concentration; CV%, coefficient of variation; geo CV%, geometric coefficient of variation; geo mean, geometric mean; mean, arithmetic mean; n miss, number of missing; PK, pharmacokinetic; SD, standard deviation; t ½, terminal half‐life; T max, time to C max; V z, volume of distribution.
Drug interaction analysis
The results of the PK parameter interaction and equivalence analysis are shown in Table 3. Comparison of the PK parameters C max, AUC0–last, and AUC0–inf in stage I (ciprofol) versus stage II (combination of sodium divalproex and ciprofol) showed that the GMR (stage II/I) was 90.0%, 88.8%, and 88.1%, respectively, with 90% confidence intervals of 85.5%–94.9%, 85.0%–92.8%, and 83.5%–92.9%, respectively (Table 3). All GMRs of the PK parameters were within the equivalent range of 80.00%–125.00%, indicating that sodium divalproex did not affect the PKs of ciprofol in healthy subjects. In addition, there was no difference in T max between the two stages (p > 0.05).
TABLE 3.
Evaluation results of pharmacokinetic interaction.
| Geo mean (stage I, stage II) | Geo mean ratio, % (stage II/stage I) | 90% confidence interval of geo mean ratio | |
|---|---|---|---|
| C max (ng/mL) | 6500, 5800 | 90.0 | (85.5, 94.9) |
| AUC0–last (h ng/mL) | 336, 299 | 88.8 | (85.0, 92.8) |
| AUC_%Extrap (%) | 363, 320 | 88.1 | (83.5, 92.9) |
Abbreviations: AUC0‐last, area under the concentration‐time curve from time of administration up to the time of the last quantifiable concentration; C max, maximum plasma concentration.
PD evaluation
The level of anesthesia was evaluated using the MOAA/S score and the BIS. The subjects' MOAA/S scores rapidly decreased after the two stages of administration, and an MOAA/S score of less than or equal to 1 was achieved at 2.000 min in stage I and at 2.010 min in stage II (Figure 3a, Table S2). The MOAA/S score then gradually recovered to grade 5, and the time to full recovery after the dose was 8.812 and 9.505 min, respectively (Figure 3a, Table S2). The results showed that the MOAA/S score time curves of subjects in stages I and II were consistent. The MOAA/S results confirmed that the PD parameters of ciprofol were not affected by sodium divalproex in healthy subjects.
FIGURE 3.
Pharmacodynamic evaluation. (a) MOAA/S score time curve. (b) BIS time curve. BIS, bispectral index; MOAA/S, Modified Observer's Assessment of Alertness and Sedation.
Similarly, the subjects' BIS scores also rapidly decreased after the two stages of administration and then gradually recovered to baseline (Figure 3b). The median time to reach the BIS peak (T BISpeak) was 3.0 min in stage I and 3.0 min in stage II, and the mean time to reach the BIS peak was 43.7 and 39.3 min, respectively (Table S3). The mean BIS AUC0–last in the two stages was 5180.53 and 4984.22, respectively (Table S3). The nearly consistent BIS time curve showed no effect of sodium divalproex on ciprofol PD parameters in healthy subjects.
Safety and AE monitoring
Among the 20 subjects in stage I, 10 grade 1 TEAEs occurred in eight (40%) subjects (Table S4), including six (30.0%) cases of abnormal findings in various examinations and three (15.0%) cases of vascular and lymphatic diseases. In stage II, 22 grade 1 TEAEs occurred in 12 (60.0%) subjects (Table S4), including 11 (55.0%) cases of abnormal findings in various examinations, four (20.0%) cases of vascular and lymphatic diseases, and two (10.0%) cases of systemic diseases and various reactions at the administration site.
Further analysis showed that four (20.0%) subjects developed five TEAEs related to ciprofol in stage I (Table S5), including two (10.0%) cases of abnormal findings in various examinations and three (15.0%) cases of vascular and lymphatic diseases. During stage II, five (25%) subjects developed seven ciprofol‐related TEAEs (Table S5), including three (15.0%) cases of abnormal findings in various examinations and four (20.0%) cases of vascular and lymphatic diseases. All the ciprofol‐related TEAEs were grade 1 in severity (Table S6). No sodium divalproex‐related TEAEs were observed. In addition, the laboratory measurements showed that only one AE (increased blood creatinine concentration) was considered to be potentially related to ciprofol (Table S7). Other AEs (Table S8) were considered possibly unrelated to either drug. There were no differences in the types of AEs related to ciprofol during the study, which indicates that concomitant use of sodium divalproex does not significantly affect the safety of ciprofol.
Some AEs characterized as clinically significant abnormal laboratory measurements occurred during the study. Specifically, these AEs included a decreased hemoglobin concentration; decreased leukocyte count; increased blood uric acid, creatine kinase, creatine kinase‐MB, lactate dehydrogenase, and aspartate transaminase concentrations; and abnormal urine erythrocytosis or urine occult blood.
Stable blood pressure was maintained in all subjects throughout the study (Figure 4a–c). All cases of ciprofol‐related hypotension (3 [15.0%] cases in stage I and 4 [20.0%] cases in stage II) resolved spontaneously without medical intervention. Therefore, there was no significant difference in the effects of ciprofol versus sodium divalproex combined with ciprofol on blood pressure.
FIGURE 4.
Vital signs, physical examination, and other safety‐related results. (a) Systolic blood pressure, (b) diastolic blood pressure, (c) mean arterial pressure, (d) heart rate, (e) respiratory rate, (f) oxygen saturation.
The heart rate fluctuated slightly before and after ciprofol administration in both stages (Figure 4d). One case of bradycardia occurred but resolved spontaneously without medical intervention. Therefore, there was no significant difference in the effects of ciprofol versus sodium divalproex combined with ciprofol on the heart rate.
The respiratory rate fluctuated slightly before and after drug administration in the two stages (Figure 4e), and no AEs occurred. There was no difference in the effects of ciprofol versus sodium divalproex combined with ciprofol on the respiratory rate. Similarly, the oxygen saturation fluctuated slightly before and after drug administration in the two stages (Figure 4f). During stage II, one subject developed oxygen desaturation, which resolved after adjusting the oxygen flow. There was no significant difference in the effects of ciprofol versus sodium divalproex combined with ciprofol on oxygen saturation. No clinically significant 12‐lead ECG abnormalities compared with baseline occurred in either stage. Only two of subjects experienced injection pain, which was rated as grade 1 and grade 2, respectively.
DISCUSSION
This single‐center, open‐label, two‐stage sequential study was performed to evaluate the drug–drug interaction between ciprofol injection and sodium divalproex extended‐release tablets in healthy Chinese subjects. This study evaluated the effects of sodium divalproex extended‐release tablets on the PKs, PDs, and safety of ciprofol injection. Eighteen of the 20 healthy subjects finally completed the study, thus meeting the requirements of the study protocol.
Ciprofol is a rapid‐onset anesthetic that takes effect in a dose‐dependent manner, and its efficacy is about four to five times that of propofol. 12 The anesthetic effect falls between that of ciprofol and that of propofol. 7 In the induction of general anesthesia for patients undergoing elective surgery, ciprofol has shown the advantages of rapid onset, minimal response to tracheal intubation, and stable vital signs. 11 , 23 The results of preclinical studies showed high affinity of ciprofol with γ‐aminobutyric acid (GABAA) receptor‐mediated chloride ion channels, indicating high selectivity of ciprofol. In addition, the incidence of ciprofol‐related cardiac function inhibition and blood pressure reduction is lower with ciprofol than propofol, suggesting a lower anesthetic risk associated with ciprofol. Additional studies showed that the effect of ciprofol on the action potential of rabbit cardiac Purkinje fibers was weaker than that of propofol within the effective concentration range. Our study produced consistent results in that all subjects maintained steady blood pressure with only slight fluctuation in the heart rate in both stages (Figure 4).
The metabolic pathway of ciprofol mainly involves hydroxylation, methyl oxidation, and glucuronic acid‐binding in rats and beagles and glucuronic acid‐binding (phase II metabolism) in humans. In general, phase II metabolic reactions enhance the hydrophilicity of a compound and deprive it of pharmacological activity. 24 Therefore, it is not necessary to adjust the dosage of ciprofol when combined with inducers or inhibitors of UGT enzymes. However, the dispensatory of propofol suggests that the plasma concentration may be increased after combination with sodium divalproex. Considering the similarities in the structure and metabolic pathway between ciprofol and propofol, the present study was designed to investigate the effect of sodium divalproex on ciprofol. The results demonstrated that combination with sodium divalproex has no significant effect on the PKs, PDs, or safety of ciprofol.
In this study, the respiratory rate, 12‐lead ECG, and oxygen saturation fluctuated slightly before and after administration in the two stages (Figure 4). The AEs resolved either spontaneously or after adjustment of the oxygen flow, indicating that there was no difference between the effects of ciprofol versus sodium divalproex combined with ciprofol on the respiratory rate and oxygen saturation. The incidence of injection pain with propofol in one study was 75.7%, 25 whereas only 10% of subjects experienced pain during the injection of ciprofol in this study. The much lower incidence of injection pain in this study may be related to the lower concentration of aqueous components in the emulsion of ciprofol. 5 All AEs involved abnormalities in various examination findings, blood vessels, and lymphatic vessels, and the severity was grade 1. No AEs involving other systems were found. There was no difference in the AEs related to the investigational drugs in the two stages. All the data demonstrated that the combination of sodium divalproex and ciprofol is safe and that sodium divalproex has no significant effect on the PKs, PDs, or safety of ciprofol.
CONCLUSION
In healthy subjects, the combination of sodium divalproex with ciprofol has no significant effect on the PK parameters of ciprofol, indicating no drug interaction between them. In addition, there was no significant effect of sodium divalproex on the PDs and safety of ciprofol. This study provides a basis for the rational clinical use of ciprofol and sodium divalproex.
AUTHOR CONTRIBUTIONS
D.Y. and P.Z. wrote the manuscript. H.L., M.Y., B.J., and M.H. designed the research. W.Z., S.H., and J.W. performed the research. Z.R. analyzed the data.
FUNDING INFORMATION
This study was sponsored by the National Major Science and Technology Project of China (No. 2020ZX09201022) and Sichuan Haisco Pharmaceutical Co., Ltd. (Chengdu, China).
CONFLICT OF INTEREST STATEMENT
The authors declared no competing interests in this work.
Supporting information
Appendix S1
ACKNOWLEDGMENTS
The authors are thankful to all subjects, investigators, and support staff who participated in this study. Finally, we thank Angela Morben, DVM, ELS, from Liwen Bianji (Edanz) (www.liwenbianji.cn), for editing the English text of a draft of this manuscript.
Yang D, Zhang W, Ruan Z, et al. Drug–drug interaction study of ciprofol and sodium divalproex: Pharmacokinetics, pharmacodynamics, and safety in healthy Chinese subjects. Clin Transl Sci. 2023;16:1972‐1981. doi: 10.1111/cts.13605
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Supplementary Materials
Appendix S1