CLINICAL STUDY: ELECTROPHYSIOLOGY
Single oral loading dose of propafenone for pharmacological cardioversion of recent-onset atrial fibrillation
Ijaz A. Khan, MDa
a Division of Cardiology, Department of Medicine, Creighton University School of Medicine, Omaha, Nebraska, USA
Manuscript received June 16, 2000;
revised manuscript received August 18, 2000,
accepted October 2, 2000.
Reprint requests and correspondence: Dr. Ijaz A. Khan, Creighton University, Cardiac Center, 3006 Webster Street, Omaha, Nebraska 68131-2044
ikhan{at}cardiac.creighton.edu
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Abstract
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The efficacy and safety of the single dose oral loading regimen of propafenone for pharmacological cardioversion of recent-onset atrial fibrillation (AFib) was evaluated by analyzing the trials on the subject identified through a comprehensive literature search. Most of the trials used a single dose of 600 mg for oral loading. The success rates ranged from 56% to 83%, depending on the duration of AFib and follow-up after drug administration. The conversion time ranged from 110 ± 59 to 287 ± 352 min, depending on the duration of observation after drug administration. The single dose oral loading regimen of propafenone was significantly more efficacious than placebo in the first 8 h after administration but not at 24 h. Compared with the intravenous regimen, the oral regimen resulted in fewer conversions in the first 2 h, but both regimens were equally efficacious afterward. The oral propafenone regimen was as efficacious as the single dose oral loading regimen of flecainide but was superior to those of quinidine and amiodarone. The adverse effects reported were transient arrhythmia, reversible QRS-complex widening, transient hypotension and mild noncardiac side effects. The transient arrhythmias were chiefly at the time of conversion and included appearance of atrial flutter, bradycardia, pauses and junctional rhythm. No life-threatening proarrhythmic adverse effects were reported. The single oral loading dose of propafenone appears to be highly effective for conversion of recent-onset AFib, with a relatively rapid effect within 2 to 3 h and freedom from serious adverse effects.
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Abbreviations and Acronyms
| | AFib | = atrial fibrillation | | AFl | = atrial flutter | | SD | = standard deviation |
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Atrial fibrillation (AFib) is the most common, clinically significant arrhythmia (1–3). The symptoms in AFib are chiefly governed by the fast ventricular rates, which can be controlled by using the atrioventricular node-blocking drugs or, ideally, by converting AFib to sinus rhythm (3–5). Traditionally, the initial treatment of AFib has been limited to controlling ventricular rates by using the atrioventricular node-blocking drugs and waiting for spontaneous conversion to sinus rhythm (6–8). However, restoration of sinus rhythm by early cardioversion will result in early alleviation of the patient’s symptoms, will lower the incidence of thromboembolism, will eliminate the need for long-term use of the atrioventricular node-blocking drugs and will possibly result in earlier discharge from the hospital (9). The electrophysiological remodeling, resulting primarily from changes in atrial refractoriness, starts taking place within a few hours of the persistent AFib and decreases the chances of successful conversion to sinus rhythm; therefore, attempts should be made to establish sinus rhythm as early as possible (10).
The rate of spontaneous conversion to sinus rhythm within the first 24 h is 30% to 50%, depending on the duration of the AFib, and can be increased to 70% to 80% by pharmacological cardioversion and to 80% to 90% by electrical cardioversion (9,11,12). The pharmacological cardioversion of recent-onset AFib carries the advantage of being simpler, more convenient and free of the need for sedation (9,12). The drugs that have been used to convert recent-onset AFib to sinus rhythm are class IA, class IC and class III antiarrhythmic agents (9,13–16). The class IC agents, propafenone and flecainide, have the advantage of convenient, single oral loading dose administration with minimum side effects (13–15,17). Propafenone is a potent sodium channel blocker with weak beta-adrenergic blocking and calcium channel blocking activities (class IC, II, IV) (18–20). Based on the available literature, propafenone administered as a single dose oral loading agent, if not contraindicated, is a useful first line agent for the pharmacological cardioversion of recent-onset AFib with a favorable side effect profile (21–36).
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Pharmacokinetics
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More than 95% of orally administered propafenone is absorbed through the gut, and the time to peak serum concentration after ingestion is 2 to 3 h (20,37). Propafenone is 95% protein bound, and the metabolism is 99% hepatic with an elimination half-life of 2 to 12 h (38,39). The pharmacokinetics of propafenone is favorable for a single loading-dose administration. Propafenone undergoes extensive first-pass hepatic metabolism by cytochrome P450 2D6 to 5-hydroxypropafenone (37). The 5-hydroxypropafenone is equivalent to propafenone as a sodium channel blocker but is less potent as a beta-blocker (40). The N-desalkylpropafenone is another metabolite of propafenone and is formed by the non-P450 2D6 mediated metabolism. This compound is less potent as a sodium channel blocker and as a beta-blocker. The full antiarrhythmic effect of propafenone depends not only on the parent compound but also on these metabolites, which provide a strong rationale for the use of the single-dose, oral loading regimen.
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Data collection
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The Medline (National Library of Medicine) search of the English-language literature was performed to identify the trials evaluating the use of oral loading propafenone for pharmacological cardioversion of recent-onset AFib. The trials studied were selected if they had compared the oral loading propafenone with placebo, intravenous propafenone or other oral loading antiarrhythmic agents. The references to the articles were examined for additional studies. All trials were examined, and data were manually extracted to provide a brief, but comprehensive, overview of the efficacy and safety of the oral loading regimen of propafenone for cardioversion of recent-onset AFib.
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Clinical trial information: efficacy
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Single dose oral loading propafenone versus placebo.
Efficacy of the single oral loading dose of propafenone for pharmacological cardioversion of recent-onset AFib has been documented by different placebo-controlled trials (21–23,25–29,31–33,35). The success rate varies from 58% to 83%, depending on the duration of AFib and follow-up after administration of the drug (21–23,25–29,31–33,35). The mean conversion time ranges from 110 ± 59 to 287 ± 352 min, depending on the duration of follow-up (21–23,25–29,31–33,35). Boriani et al. (21) evaluated this regimen (600 mg propafenone) in 240 patients with recent-onset AFib ( 7 days) in a multicenter, randomized, placebo-controlled trial. Conversion to sinus rhythm was significantly better in the propafenone treated patients with 3-h and 8-h conversion rates of 45% and 76% in the propafenone group versus 18% and 37% in the placebo group (p < 0.001 at both 3 h and 8 h). The conversion time was 181 ± 118 (mean ± standard deviation [SD]) min in the propafenone and 181 ± 112 (mean ± SD) min in the placebo group (p = NS). Patients older than 80 years, those with heart failure greater than New York Heart Association functional class II, recent myocardial infarction (<6 months), unstable angina pectoris, complete bundle branch block, previous electrocardiographic evidence of second- or third-degree atrioventricular block or bifascicular block, sick sinus syndrome, renal or hepatic failure, severe hypoxia, severe metabolic disturbance, thyroid dysfunction, hypokalemia, ventricular rate <70 beats/min or on antiarrhythmic therapy were excluded from the trial. More or less similar exclusion criteria have been used in most of the trials evaluating the efficacy of the single dose oral loading regimen of propafenone.
The 600-mg dose of propafenone is used for oral loading because it has been shown that 450 to 600 mg of oral propafenone results in clinically effective plasma levels (41). In another randomized, double-blind, placebo-controlled trial (22) (n = 55 patients), propafenone dose was weight-titrated (450 mg for 50 to 64 kg, 600 mg for 65 to 85 kg and 750 mg for >85 kg body weight). Atrial fibrillation of 7 days was defined as recent-onset AFib. The patients were followed for 24 h. The 2-h and 6-h conversion rates were 41% and 65%, respectively, and were significantly better than those of the placebo group (8% and 31%) (p = 0.005 and 0.015). The 12-h conversion rates were 69% in the propafenone group and 42% in the placebo group with a trend toward the difference (p = 0.06). The 24-h conversion rates were not significantly different between both groups (propafenone, 79% vs. placebo, 73%). The number of patients who received 450 mg (n = 4) and 750 mg (n = 3) doses was not sufficient to empower the study to evaluate the effect of weight-based dose adjustment on the efficacy of the drug.
In another randomized, placebo-controlled trial, Botto et al. (23) compared 450-mg and 600-mg dosage regimens, irrespective of the body weight of the patient (n = 105). Atrial fibrillation of 7 days was defined as recent-onset AFib. The patients were followed for 24 h. The 2-h conversion rate with the 600-mg dosage regimen was significantly higher than it was for those with the 450-mg dosage regimen (p = 0.001) and the placebo (p = 0.004). The 450-mg regimen was not significantly better than the placebo at 2 h. The 4-h, 8-h and 24-h conversion rates were not significantly different between both dosage regimens. Both 450-mg and 600-mg regimens were significantly better than the placebo at 4 (p < 0.04 and p < 0.001) and 8 h (p < 0.01 and < 0.04) but not at 24 h. The time to sinus conversion in the first 4 h was 176 ± 56 (mean ± SD) min with the 450-mg regimen and 110 ± 59 (mean ± SD) min with the 600-mg regimen. The trial demonstrated that the 600-mg regimen was more efficacious and resulted in earlier conversion to sinus rhythm.
The efficacy of the single oral loading dose of the propafenone administration has also been demonstrated in nonrandomized trials (24,30). A nonrandomized study by Ergene et al. (24) demonstrated that the 8-h conversion rate with the use of a 600-mg single oral dose of propafenone for the recent-onset subjects with AFib (<72 h) was 78%, with a conversion time of 2.4 ± 0.9 (mean ± SD) h. In this study, the duration of the AFib was found as a single, significant predictor of the successful conversion to sinus rhythm.
Oral versus intravenous regimens of propafenone.
The efficacy of the oral loading dose regimen versus the intravenous regimen of the propafenone administration for conversion of patients with recent-onset AFib has been evaluated in different randomized trials (27–29). The intravenous regimen has been found superior in the first few hours of the drug administration, but there has been no difference in the efficacy of both of the regimens at the longer observation periods. In a randomized, placebo-controlled trial involving 87 patients with recent-onset AFib (7 days), Boriani et al. (27) compared single oral loading dose regimen (600 mg) with an intravenous regimen (2 mg/kg bolus followed by 0.0078 mg/kg/min). The 1-h conversion rate was significantly higher with use of the intravenous regimen (28%) than it was with the use of the oral regimen (3%) (p = 0.05), but 3- and 8-h conversion rates were not significantly different between both regimens. The 3-h conversion rate with the oral propafenone was 55% compared with 41% with the intravenous propafenone (p = NS) and 10% with the placebo (p < 0.001 oral; p < 0.02 intravenous). The 8-h conversion rate with oral propafenone was 69% compared with 66% with intravenous propafenone (p = NS) and 24% with the placebo (p < 0.005 oral; p < 0.005 intravenous). The conversion time was 163 ± 114 (mean ± SD) and 138 ± 140 (mean ± SD) min with oral and intravenous regimens, respectively (p = NS).
In another randomized, placebo-controlled, crossover trial, Botto et al. (28) compared the oral regimen (600 mg single dose) with the intravenous regimen (2 mg/kg bolus followed by 0.0078 mg/kg/min for 2 h) in 123 patients with recent-onset AFib (<72 h). The patients were followed for 16 h. If AFib persisted at 8 h in the study (phase I), the patients on the active drug regimens received the alternative formulation in the dose similar to that used in the stage I (crossover); the nonresponders in the placebo group were continued on placebo (phase II). The intravenous regimen was significantly superior to the oral loading regimen at 1-h observation time (48% vs. 15%, p < 0.05) but not at longer observation periods of 4 and 8 h. Rather, at 4 and 8 h, the conversion rates were higher with the use of oral regimen with a statistically significant difference at 8 h (71% vs. 50% at 4 h, p = NS; 78% vs. 53% at 8 h, p < 0.03). In phase II, at 1 h, the conversion rate in the nonresponders to the intravenous regimen who were given the oral regimen was similar to that in the nonresponders of the oral regimen who were given the intravenous regimen (12% vs. 13%, p = NS) but was significantly better at 4 and 8 h (65% vs. 13%, p = 0.01 and 76% vs. 25%, p = 0.004). The mean conversion time within the first 4 h of the phase I was shorter with use of the intravenous regimen than it was with the use of the oral regimen (25 ± 15 vs. 167 ± 166 min, p < 0.001). In this trial, the intravenous infusion was given for 2 h and was not continued until the patient converted to sinus rhythm or the study period was over, which could be a possible cause of the lower success rates with the intravenous regimen at the longer observation periods.
The efficacy of propafenone administration (both by intravenous and oral routes) for short-term conversion of AFib was analyzed in a meta-analysis published in 1998 (30). Twenty-seven trials were analyzed, of which 19 used intravenous propafenone, 6 used oral loading propafenone and 2 used a combination of oral and intravenous dosing regimens. A total of 1,843 patients were treated with propafenone in these trials. The meta-analysis compared the efficacy of the oral regimens with that of the intravenous regimens and of both the oral and intravenous regimens combined with that of the placebo. It concluded that the intravenous regimen, compared with the oral regimen, resulted in a more rapid conversion to sinus rhythm (p < 0.05 both at 1 and 2 h), but this advantage was no longer apparent after 4 h of initiation of therapy. The patients treated with propafenone (oral and intravenous combined) were more likely to convert to sinus rhythm than those who received placebo, with a treatment benefit of 31.5% at 4 h (p < 0.01) and 32.9% at 8 h (p < 0.01). Propafenone therapy (oral and intravenous combined) was not significantly different from that of the placebo after 24 h of administration of the drug. The efficacies of the oral and the intravenous regimens were not compared with those of the placebo individually.
Propafenone versus other oral loading drugs.
The oral loading regimen of propafenone for conversion of the recent-onset AFib was compared with the oral loading regimens of flecainide, quinidine and amiodarone, and it was found to be as effective as that of the flecainide and superior to those of quinidine and amiodarone (29,31–35). The single oral regimen of propafenone (600 mg) was compared with that of flecainide (300 mg) in a randomized, placebo-controlled trial (31) involving 181 patients with recent-onset AFib (7 days). The 3-h conversion rates were 51%, 59% and 18%, and the 8-h conversion rates were 72%, 78% and 39% in the propafenone, flecainide and placebo groups, respectively. The 3-h and 8-h conversion rates were not statistically different between the propafenone and flecainide treatment groups. The conversion time was 165 ± 119 (mean ± SD) min with propafenone use and 158 ± 109 (mean ± SD) min with flecainide use (p = NS).
In another randomized, placebo-controlled trial (n = 87 patients) (33), the oral propafenone regimen (600 mg loading, followed by 300 mg every 8 h for 48 h) was compared with the digoxin plus quinidine regimen for conversion of recent-onset AFib (AFib of 8 days). Quinidine administration was started 6 h after the initiation of the intravenous administration of digoxin and was given as a 300-mg dose followed by 150 mg every 3 h for 9 h and then 150 mg every 8 h for a total loading of 1,350 mg. The patients were followed for 48 h. The conversion to sinus rhythm with the propafenone regimen was significantly better than it was with the digoxin plus quinidine regimen at 6 and 12 h (62% vs. 38%, p < 0.05 and 83% vs. 48%, p < 0.05, respectively), but there was no difference at 24 and 48 h. The conversion time with the 48 h of follow-up was 167 ± 238 (mean ± SD) min for the propafenone group and 648 ± 631 (mean ± SD) min for the digoxin plus quinidine group (p < 0.01).
Blanc et al. (34) compared the efficacy of the oral propafenone with that of oral amiodarone for conversion of recent-onset AFib (<2 weeks). In this randomized trial, the patients in the propafenone group received a single oral loading dose of 600 mg propafenone and, if necessary, a repeat dose of 300 mg after 24 h; and the patients in the amiodarone group received amiodarone 30 mg/kg and, if necessary, a repeat dose of 15 mg/kg after 24 h. The patients were followed for 48 h. The 4-h conversion rate was significantly higher in the propafenone-treated patients (37% vs. 16%, p < 0.05), but by 24 h the difference was no longer statistically significant (56% vs. 47%). The median conversion time with propafenone use was significantly shorter than it was with amiodarone (2.4 vs. 6.9 h, p = 0.05). The success rate was lower in this trial compared with the other propafenone trials, and this could be secondary to the longer time duration used to define the recent onset of AFib (two weeks). In a subgroup analysis based on the duration of AFib, 84% of all the patients with AFib of <2 days duration converted to sinus rhythm compared with 45% of those with AFib of  2 days (p = 0.001) (34). The duration of AFib has been shown to be a significant predictor for the successful conversion to sinus rhythm with use of the single oral loading dose regimen of propafenone (24).
Propafenone use in hypertension and structural heart disease.
In the trials where patients with systemic hypertension and stable structural heart disease were included in the study, it was demonstrated that the efficacy of propafenone was not affected by the presence of systemic hypertension or structural heart disease (21,24,35). In the trial by Boriani et al. (21), of 119 patients in the propafenone treatment arm, 37 had systemic hypertension, and 32 had structural heart disease, including coronary artery disease, valvular heart disease, cardiomyopathy and congenital heart disease. The 8-h conversion rates in patients with hypertension, with structural heart disease and without structural heart disease were 70%, 81% and 78%, respectively (p = NS). In the trial by Ergene et al. (24), most of the patients had systemic hypertension or structural heart disease, including coronary artery disease, congestive heart failure and mitral stenosis, and the presence of systemic hypertension or structural heart disease did not preclude the conversion to sinus rhythm.
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Clinical trial information: safety
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The adverse effects reported with use of the single dose oral loading regimen of propafenone were transient arrhythmia, reversible QRS-complex widening, transient hypotension and mild noncardiac side effects (21–29,31–35). The transient arrhythmias, chiefly at the time of conversion, included appearance of atrial flutter (AFl), bradycardia, pauses and junctional rhythm. No life-threatening proarrhythmic adverse effects were reported. The effective concentration of propafenone after an oral dose for patients with acute AFib is significantly lower than that during the chronic administration for patients with chronic AFib, which may be a reason for the lack of serious adverse events with the use of a single oral loading dose (37). All of the reported adverse events, including proarrhythmic ones, were transient.
In most of the trials, the incidence of various proarrhythmic adverse effects in propafenone treated patients was not higher than that in the placebo treated patients. In the trial by Boriani et al. (n = 240 patients) (21), AFl or tachycardia lasting 1 min appeared in eight patients (7%) receiving propafenone and in seven patients (6%) receiving placebo, regardless of heart disease status. Among these patients, in all except one the atrioventricular conduction ratio was 2:1 with ventricular rates 140 beats/min; one patient in the placebo group demonstrated 1:1 atrioventricular conduction with a ventricular rate of 240 beats/min and experienced syncope. Pauses in ventricular activity lasting for 2 s were seen in one patient receiving propafenone and in three receiving placebo. In another trial by Capucci et al. (33), the AFl with 2:1 atrioventricular conduction ratios and heart rates of 150 beats/min was noted in 4 of 29 propafenone recipients and in 4 of 29 placebo recipients. In this trial, one patient in the propafenone group experienced a syncopal episode, and the electrocardiographic recording showed a wide-complex tachycardia at 220 beats/min, which lasted a few seconds and ended spontaneously. One month later, at an electrophysiological study, an AFl with 1:1 atrioventricular conduction at 220 beats/min was reproduced in this patient after the intravenous administration of propafenone.
Propafenone, being principally metabolized by the liver, may have an advantage of being useful in patients with renal disease. In a nonrandomized study of 24 patients with AFib and chronic renal failure (42), administration of intravenous propafenone resulted in conversion to sinus rhythm in 21 patients without any serious adverse effects. However, the safety of oral propafenone administration in chronic renal failure cannot be generalized from a single trial with a small number of patients who received the drug by a nonoral route.
Safety antiarrhythmic therapy evaluation trial.
The results of the Safety Antiarrhythmic Therapy Evaluation trial were published in 1999 (35). The primary end point of this multicenter, placebo-controlled trial was to evaluate the safety of the oral loading regimen of propafenone in restoring the sinus rhythm in patients with recent-onset AFib compared with the classical treatment. The trial enrolled 246 patients and randomly assigned them to one of the four treatment groups: propafenone, digoxin plus propafenone, digoxin plus quinidine and placebo. The propafenone dose used was 600 mg for patients weighing >60 kg body weight and 450 mg for patients <60 kg body weight. After 6 h, a second dose of 300 mg was given if AFib was persistent. Digoxin was given intravenously at a dose of 0.5 mg at study entry followed by 0.25 mg after 4 h and 0.125 mg after 8 and 12 h (total of 1 mg) to patients >60 kg body weight and 0.125 mg at 4 h and 0.065 mg at 8 and 12 h (total of 0.755 mg) to patients <60 kg body weight. Quinidine was given 1 h after initiating the digoxin therapy at a dose of 275 mg every 2 h for a total dose of 1,100 mg. The adverse events were classified as mild (transient and easily tolerated), moderate (causing discomfort to the patient) and severe (life-threatening or resulting in prolonged hospitalization).
None of the patients experienced severe clinical adverse events. The most common arrhythmia noted was AFl in 13 propafenone treated, 12 digoxin plus propafenone treated, 9 digoxin plus quinidine treated and 3 placebo treated patients. All of these episodes were short lasting (<30 s), were asymptomatic and were conducted with an atrioventricular conduction ratio 2:1. None of the AFl episodes was conducted to the ventricles with a 1:1 ratio. Four patients in the digoxin plus propafenone group and one patient in the digoxin plus quinidine group had asymptomatic ventricular runs of 3 or 4 beats. A complete left bundle branch block was detected in three patients in the propafenone group, two patients in the digoxin plus propafenone group and two patients in the digoxin plus quinidine group. The bundle branch block resolved spontaneously in all patients during 4 to 8 h. A reversible, asymptomatic, Wenckebach II degree sinus atrial exit block (pauses <3 s) was observed at the time of conversion in two patients in the propafenone group and in two patients in the digoxin plus quinidine group. Mild arterial hypotension developed in five patients in the propafenone group, one patient in the digoxin plus propafenone group, one patient in the digoxin plus quinidine group and one patient in the placebo group. None of these episodes was severe enough to require any pharmacological intervention. The noncardiac side effects were mild and, in the propafenone treated patients, consisted of nausea, headache, gastrointestinal disturbances, dizziness and paresthesia. The side effects in the propafenone group were not significantly different from those in other treatment groups.
Concomitant use of an atrioventricular node-blocking drug.
A need for concomitant therapy with the agents that block the atrioventricular node is unclear at the present time because patients receiving these types of agents were excluded from most of the trials. Although it could be speculated that if an AFl develops, the beta-blocking and calcium channel blocking effects of the propafenone may protect against 1:1 atrioventricular conduction; however, there is a minimum possibility that rapid atrioventricular conduction may develop, resulting in a fast ventricular response. Therefore, to abate any possibility of 1:1 atrioventricular conduction in case AFl develops, it may be prudent to administer an atrioventricular node-blocking drug before propafenone loading or to keep the patients at bed rest afterward (13). Many physicians do administer low-dose propranolol or another beta-blocker to the patients being treated with the oral propafenone in order to avoid AFl with 1:1 conduction, but studies need to be done to evaluate whether the coadministration of a beta-blocker with the oral loading dose of the propafenone will have added benefit in addition to that provided by the inherent atrioventricular node-blocking properties of the propafenone.
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Contraindications
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Based on the previous experience with propafenone, its administration is contraindicated in patients with congestive heart failure; severe systolic dysfunction; sinoatrial, atrioventricular or intraventricular disorders of impulse conduction; sinus node dysfunction; hypotension; unstable angina; acute or recent myocardial infarction; severe hepatic or renal failure; hypokalemia; thyroid dysfunction; bronchospastic disorder; and severe metabolic disturbances (43–46). Patients with these conditions were excluded from almost all the trials evaluating efficacy and safety of the oral loading dose regimen of propafenone for conversion of recent-onset AFib.
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Conclusions
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Because of its high rate of effectiveness, a relative rapid effect within 2 to 3 h and the simplicity of administration, the single oral loading dose of propafenone may be considered to be among the first-line treatments used for conversion of recent-onset AFib. Most of the data on the use of single oral loading of propafenone is for a single dose of 600 mg. The success rate of this regimen ranges from 56% to 83%, depending on the duration of the AFib and follow-up after drug administration. The conversion time varies from 110 ± 59 to 287 ± 352 min, depending on the duration of the observation after drug administration. The single oral loading dose of propafenone is significantly more efficacious than placebo in the first 8 h after administration of the drug, but the difference does not remain statistically significant at 24 h.
The use of the oral loading regimen of propafenone in patients with hypertension and stable structural heart disease is not supported by a large body of data, although, in trials that recruited patients with hypertension and stable structural heart disease, the efficacy and side effect profile of this regimen in these patients was not different from the patients without hypertension or structural heart disease. The data on the use of the single oral loading dose of propafenone in patients already taking propafenone or another antiarrhythmic drug has not been reported.
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Abstract
Pharmacokinetics