Lippincott Williams & Wilkins



Supplemental Appendix:Supplemental Appendix Table 1: Toxicities Assessed to be at Least ‘Possibly Related’ to EFVNon-neurologic Toxicity: n=10 participantsTypeNCYP2B6 516 GenotypeGradeCommentsWeek 2 AUC > 180 Elevated Bicarbonate 2GT2Week 12NOGG2Week 16NOLow Absolute Neutrophil Count (ANC)4GT3Week 12NOGT*3Week 8, also had neurologic toxicity (see below) YESGT4Week 3, also grade 2 alkaline phosphatase, treatment discontinued due to high AUCYESTT4Week 4, treatment discontinued due to toxicityYESRash 2GG2 Week 1 NOGT2 Week 2 NOLow Hemoglobin (HgB)1TT3Week 5, also had grade 2 pallor, treatment discontinued due to high AUCYESHigh serum glutamic-pyruvic transaminase(SGPT) 1TT2Week 24 YESNeurologic Toxicity: n=6 participantsTypeCYP 2B6 516 GenotypeGradeCommentsWeek 2 AUC > 180 Lethargy/Sleepiness 5GG31st day of treatment, also had simple febrile seizure 8 days after treatment started; treatment discontinued due to toxicityNO GT2 1 day after treatment started, with grade 1 irritabilityNOGG2 3 days after treatment started, with grade 2 abdominal painNO TT1 1 day after treatment startedYESGT*13 episodes grade 1 dizziness: 1 day after treatment started, resolved after 4 days;at week 2, resolved after 2 days; at week 3, resolved after 5 days YESSleep Disturbance 1GG1Week 11NO* represents the same participant. Overall, there are n=15 distinct participants who had toxicities assessed to be possibly related to EFV. Supplemental Appendix Table 2: AUC and C24: P1070 V2 PK Data and Estimated FDA ExposuresEFAVIRENZ AREA UNDER THE (AUC)CYP2B6 516 GG/GT n=38Median AUC (mcg*h/mL)[IQR]# (%) below AUC target ?# (%) meeting AUC target??# (%) above AUC target ???P1070 dosing*107.5[57.24, 132.90]4 (11%)31 (82%)3 (8%)FDA dosing** 51.92[28.62, 66.45]12 (32%)24 (63%)2 (5%)CYP2B6 516 TT n=9P1070 dosing**102.5[63.71, 145.48]0 (0%)8 (89%)1 (11%)FDA dosing **205[162.24, 290.97]0 (0%)4 (44%)5 (56%)EFAVIRENZ 24 HOUR CONCENTRATION LEVELS (C24)CYP2B6 516 GG/GT n=38Median C24 (mcg/mL)[IQR]# w/ Estimated Plasma C24 <1 mcg/mL# w/ Estimated Plasma C24 in [1-4] mcg/mL#w/ Estimated Plasma C24 >4 mcg/mLP1070 dosing*1.9[0.89, 3.22]10 (26%)22 (58%)6 (16%)FDA dosing** 0.9[0.45, 1.51]22 (58%)14 (37%)2 (5%)CYP2B6 516 TT n=9P1070 dosing**4.0[2.18, 5.83]0 (0%)4 (44%)5 (56%)FDA dosing **8.06[5.10, 11.67]0 (0%)0 (0%)9 (100%)*Observed values ** Predicted values? Estimated Plasma AUC <35 mcg*h/mL??Estimated Plasma AUC 35-180 mcg*h/mL??? Estimated Plasma AUC >180 mcg*h/mLSupplemental Appendix table 3: Supplemental toxicity table for grading severity of neurologic adverse eventsFor the purposes of P1070, the following parameter and grading criteria were used in conjunction with the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, dated December 2004 in grading neurologic adverse events. This parameter supersedes Row 1 (alteration in personality-behavior or in mood) and Row 2 (altered mental status) of the neurologic section of the DAIDS Toxicity Table.Grade 1Grade 2Grade 3Grade 4Sleepiness, lethargy, irritabilityTransiently lethargic, irritable or fussy (above usual norm), but otherwise normal routine.More sleeping or crying than usual, not on normal routine without alternate explanation.> 7 days of a change in personality without alternate explanation and confirmed by objective observation by study staff OR Somnolent, needs to be stimulated to take feedings.Somnolent, unable to be stimulated to take feedings. ORInconsolable irritability or crying with unusually high pitch or screaming for > 3 hours Supplemental Appendix Figure 1 : AUCs from P1070 Participants By WeightParticipants with CYP2B6 516TT genotype are shown as open symbols. CYP2B6 516TT participants' AUCs were adjusted to reflect the modeled levels using the lower EFV TT dosing used in version 2. Supplemental Appendix Figure 2: Overall (GG/GT and TT) Virologic Response (ITT Analysis) Supplemental Appendix Figure 3: Overall (516GG/GT and 516TT) Virological Response (As Treated Analysis) ................
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