Bioavailability of oxycodone by mouth in coronary artery bypass surgery patients – a randomized trial

Figures & data

Figure 1. Flow chart. CECC = conventional extracorporeal circulation; OPCAB = Off-pump coronary artery bypass surgery; PREOP = preoperative day; POD = postoperative day.

Table 1. Patient characteristics.

Parameter	Conventional extracorporeal circulation groups		Off-pump groups
	Samples on POD1 and POD3	Samples on POD2 and POD4	Samples on POD1 and POD3	Samples on POD2 and POD4^h
	n = 6	n = 6	n = 6	n = 6
Sex: male/female	6/–	5/1	6/–	5/1
Age, years	63 [57–73]	61 [50–73]	66 [59–72]	66 [56–70]
Height, m	1.73 [1.63–1.83]	1.72 [1.71–1.82]	1.75 [1.70–1.84]	1.78 [1.61–1.82]
Weight, kg	86 [60–102]	93 [85–99]	81 [65–98]	81 [65–104]
BMI, kg/m^2	27.6 [22.4–34.9]	30.4 [29.1–32.4]	25.8 [21.2–33.7]	25.2 [22.2–35.0]

Data are presented as the number of cases or median [minimum – maximum].

Abbreviations: POD, postoperative day; BMI, body mass index.

Figure 2. Plasma concentrations of oxycodone in the CECC-group with blood samples in the preoperative, and 1^st and 3^rd postoperative days.

Figure 3. Plasma concentrations of oxycodone in the CECC-group with blood samples in the preoperative, and 2^nd and 4^th postoperative days.

Figure 4. Plasma concentrations of oxycodone in the OPCAB-group with blood samples in the preoperative, and 1^st and 3^rd postoperative days.

Figure 5. Plasma concentrations of oxycodone in the OPCAB-group with blood samples in the preoperative, and 2^nd and 4^th postoperative days.

Table 2. Pharmacokinetic parameters for 10 mg oxycodone hydrochloride (9.0 mg free base) after coronary artery by-pass surgery in the different treatment groups.

Group	Study day	n	AUC0–24 ^a	Corrected AUC0–24 ^b	Cmax ^a	tmax	t1/2
			(ng·min/mL)	(ng·min/mL)	(ng/mL)	(min)	(min)
1 (CECC)	Preoperative	6	4250 [3590–6570]	4250 [3590–6570]	6.4 [5.7–10.0]	180 [120–270]	387 [299–481]
	POD1	6	3650 [2760-4550]	3620 [2760–4490]	6.9 [4.2–9.8]	630 [270–1420]	–
	POD3	6	7060 [6450-7270]^§§	6130 [5610–6800]^§	10.6 [7.7–11.8]*^,§	120 [60–720]	437 [376–475] (n = 5)
2 (CECC)	Preoperative	6	3830 [3560-6070]	3830 [3560–6070]	6.0 [5.1–9.4]	180 [30–180]	394 [313–496]
	POD2	6	5600 [3790-7250]	4960 [3140–6070]	8.8 [7.6–10.3]	180 [120–360]	346 [286–968]
	POD4	6	6220 [5270-8610]*	5500 [4920–6990]	10.3 [7.8–12.7]*	180 [120–270]	330 [293–348]
3 (OPCAB)	Preoperative	6	4560 [4280-6480]	4560 [4280–6480]	7.2 [5.7–9.3]	225 [120–360]	417 [378–531]
	POD1	6	3740 [1390-5400]	3690 [1360–5320]	5.6 [1.7–10.2]	1020 [720–1410]	–
	POD3	6	8000 [5620-9520]^§§	5990 [3990–8330]^§	10.1 [8.1–13.2]^§	315 [180–720]	462 [311–463] (n = 5)
4 (OPCAB)	Preoperative	6	3720 [1930-4870]	3720 [1930–4870]	6.5 [4.0–7.1]	150 [60–270]	309 [244–497]
	POD2	6	4570 [3370-8570]	4030 [2100–5990]	8.4 [3.6–12.7]	230 [120–720]	333 [263–394] (n = 4)
	POD4	5	4640 [2190-8170]	4410 [2040–7150]	7.3 [5.0–12.8]	270 [120–540]	374 [195–472]

Data are presented as the median [minimum–maximum] (n for t_1/2 if different from the group size).

^aBased on the observed concentrations, ^bthe carry-over from the previous doses were subtracted as described in Materials and methods. Abbreviations: POD, postoperative day; CECC, conventional extracorporeal circulation; OPCAB, off-pump coronary artery bypass surgery. Significances: *p < .05 vs. Preoperative day; ^§p < .05 vs. POD1; ^§§p < .01 vs. POD1.

Table 3. Peak concentrations of main oxycodone metabolites in plasma.

Group	Study day	Cmax (ng/mL)
		Noroxycodone	Oxymorphone	Noroxymorphone
1 (CECC)	Preoperative	6.7 [5.0–10.4]	0.10 [0.07–0.15]	1.3 [0.5–3.1]
	POD1	6.3 [2.7–12.5]	0.12 [0.10–0.19]	1.5 [0.7–1.9]
	POD3	6.0 [3.5–10.1]	0.23 [0.13–0.42]	1.3 [0.8–3.3]
2 (CECC)	Preoperative	7.0 [4.6–8.9]	0.13 [0.0–0.18]	1.0 [0.5–1.5]
	POD2	6.0 [3.2–11.9]	0.21 [0.0–0.30]	1.4 [0.27–1.8]
	POD4	6.3 [2.7–12.5]	0.12 [0.10–0.19]	1.5 [0.7–1.9]
3 (OPCAB)	Preoperative	6.5 [4.5–11.8]	0.18 [0.0–0.26]	1.9 [0.27–3.0]
	POD1	5.3 [1.7–6.8]	0.14 [0.0–0.23]	1.1 [0.18–1.9]
	POD3	5.0 [2.5–9.9]	0.39 [0.0–0.86]	2.1 [0.5–2.9]
4 (OPCAB)	Preoperative	8.9 [4.6–10.4]	0.14 [0.0–0.29]	1.6 [0.27–3.1]
	POD2	9.4 [2.3–17.5]	0.18 [0.0–0.54]	1.7 [0.27–3.8]
	POD4	5.3 [2.5–9.2]	0.28 [0.0–0.69]	1.4 [0.45–2.0]

Data are presented as the median [minimum–maximum].

Abbreviations: C_max, peak concentration; POD, postoperative day; CECC, conventional extracorporeal circulation; OPCAB, off-pump coronary artery bypass surgery.

Figure 6. Predicted-corrected visual predictive check (PC-VPC) for the final oxycodone PK model. Plots show median (solid) and 90% intervals (dashed lines). The y axis is presented on a logarithmic scale. Left hand plot shows all prediction corrected observed oxycodone concentrations. Right hand plot shows prediction corrected percentiles (10%, 50%, and 90%) for observations (grey dashed lines) and predictions (red dashed lines) with 95% confidence intervals for prediction percentiles (median, pink shading; 5th and 95th blue shading).

Table 4. Oxycodone population pharmacokinetic parameter estimates.

			PPV (%)
Parameter	Estimate	95%CI	BSV	BOV
V1 (L/70 kg)	134	90.9, 157	176	70.9
V2 (L/70kg)	81.9	72.3, 105	83.6
CL (L/h/70 kg)	43.3	38.5, 49.5	37.0	32.1
Q (L/h/70kg)	155	151, 182	86.7
Relative bioavailability	0.53	0.48, 0.60	56.6
tlag (hours)	0.27	0.25, 0.33	–
Flag	11.8	10.1, 15.1	–
LagT (days)	1.25	1.2, 1.4	–
tabs (hours)	1.55	1.4, 2.2	–
Fabs	3.91	2.6, 4.6	–
RUV additive (ng/mL)	0.082	0.035, 0.089	ηPPV_RUV 0.44
RUV proportional (%)	21.4	19, 33	–

Parameter estimates are presented as the medians.

Abbreviations: V, volume of distribution; CL, clearance; Q, intercompartmental clearance; tlag, absorption lag-time; Flag is a scaling parameter applicable to tlag on POD1; tabs, absorption half-time; Fabs is a scaling parameter applicable to tabs on POD1; RUV, residual unidentified variability; CI, confident interval; PPV% (PPV%=√variance × 100), population parameter variability; BSV, between subject variability; BOV, between subject variability.

Figure 7. Pain scores in the two groups at rest (A) and with cough (B) in the two groups. Data are presented as the mean and standard deviation.

Figure 8. Morphine consumption via IV PCA pump in the two groups. Data are presented as the mean and standard deviation.

Data availability statement

The data that support the findings of this study are available from the corresponding author, HK, upon reasonable request.