Azithromycin plus chloroquine: combination therapy for protection against malaria and sexually transmitted infections in pregnancy

Figures & data

Table 1. Optimal IPTp drug profile.

The optimal IPTp therapy would be a combination of two molecules that:
✓	Exhibit similar time above minimum inhibitory concentrations
✓	Support a once per month dosing regimen (≤ 2 doses)
✓	Have different mode of actions to reduce resistance selection
✓	Are active against asexual & sexual stages
✓	Are not necessarily rapid acting*
✓	Are either a fixed dose or loose combination
✓	Different from first line treatment for symptomatic malaria
✓	Ideally active against other treatable maternal health problems, e.g. STI/RTI, maternal-fetal transmission of infection
✓	Are safe during all the pregnancy, although pregnant women are unlikely to receive the first dose of IPTp in the first trimester
✓	Cost as little as possible per pregnancy with prices that are in line with current price estimates for artemisinin combination therapy (ACT)
Note: There are no new classes of medicines with plasma exposures above MIC for 28 days. Such exposure is most likely to be achieved by slow release depot formulations which would require molecules with doses of less than 10 mg/day. No such compounds currently exist.

*Symptomatic women are treated with ACTs.

Source: Duparc, S. (2011). Personal communication. Medicines for Malaria Venture, Geneva, Switzerland.

Box 1. Drug summary.

Drug name (generic)	Azithromycin-chloroquine
Phase	Phase III
Indication	Intermittent preventive treatment of malaria in pregnancy
Pharmacology description/mechanism of action	Azithromycin is a slow-acting macrolide that targets the 70S ribosomal subunit of the apical complex in susceptible microorganisms including malaria parasites Chloroquine is a rapidly absorbed 4-aminoquinoline that accumulates in digestive vacuoles, binds to hematin and prevents its expulsion from sensitive malaria parasites
Route of administration	Oral/Per os (PO)
Molecular formula	Azithromycin – C38H72N2O12
Chemical structure
	Chloroquine – C18H26ClN3
Pivotal trial(s)	ClinicalTrials.gov Identifier: NCT01103063 ‘Evaluate Azithromycin Plus Chloroquine And Sulfadoxine Plus Pyrimethamine Combinations For Intermittent Preventive Treatment Of Falciparum Malaria Infection In Pregnant Women In Africa’ [113]

Table 2. Efficacy of azithromycin, chloroquine or the combination against P. Falciparum infection observed among non-pregnant adults and children in recent studies.

Country	Years of study [Ref.]	Drug regimen	Sample size	PCR-unadjusted APR at day 28 (95% CI)	PCR-adjusted APR at day 28 (95% CI)
Western Kenya	2004 [81] Pfizer 82563	1 g AZ plus 600 mg CQ days 0, 1, 2	5	NA	100% (NA)
		600 mg CQ days 0, 1, 2 plus AZ placebo	7	NA	87.5% (59.8 – 100)
Malawi (children)	2005 [74] Laufer et al.	10 mg/kg CQ days 0, 1 and 5 mg/kg CQ day 2	80	NA	98.7% (96.3 – 100)*
		SP (1.25 mg/kg and 5 mg/kg) day 0	87	NA	18.4% (10.3 – 26.5)*
Ghana, Kenya, Mali, Uganda, Zambia	2004 – 2006 [83] O26-44 [81] Pfizer 82576	1 g AZ and 600 mg CQ days 0, 1, 2 plus MQ placebo day 0	103	NA	98.1% (95.4 – 100)
		500 mg AZ and 600 mg CQ days 0, 1, 2 plus MQ placebo day 0	Arm suspended: inadequate efficacy of regimen outside of Africa
		750 mg MQ and 500 mg MQ day 0 plus placebo AZ and CQ days 0, 1, 2	103	NA	99.0% (97.1 – 100)
Burkina Faso, Ghana, Kenya, Mali, Senegal, Zambia	2006 – 2007 [81] Pfizer 367653	1 g AZ and 600 mg CQ days 0, 1, 2	107	NA	100% (NA)
		750 mg MQ and 500 mg MQ day 0	112	NA	99.1% (97.4 – 100)
Guinea-Bissau (children)	2006 – 2008 [79] Ursing et al.	50 mg/kg CQ in 6 doses days 0, 1, 2	158	NA	95.1%* (91.5 – 98.4)
		AL (20 mg/120 mg) up to 4 tablets at 0, 8, 24, 36, 48 and 60 h	168	NA	96.6%* (93.6 – 99.2)
India	1998 – 2001 [18] Dunne et al. 2005b	1 g AZ plus CQ placebo days 0, 1, 2	15	33.3% (9.5 – 57.2)*	NA
		600 mg CQ days 0, 1 plus placebo AZ day- 0, 1, 2 and CQ day 2	15	26.7% (4.3 – 49.1)*	NA
		1 g AZ days 0, 1, 2 and 600 mg CQ days 0, 1 and 300 mg CQ day 2	63	96.8% (92.5 – 100)*	NA
India	2004 – 2005 [129] O26-45 [81] Pfizer 74841	1 g AZ days 0, 1, 2 and 600 mg CQ day- 0, 1 and 300 mg CQ day 2	73	83.6% (75.1 – 92.1)	NA
		500 mg AZ and 600 mg CQ days 0, 1, 2 plus placebo 500 mg AZ days 0, 1, 2	59	66.1% (54.0 – 78.2)	NA
		600 mg CQ days 0, 1 and 300 mg CQ day 2 SP (1.5 g/75 mg) day 0	72	94.4% (89.2 – 99.7)	NA
Indonesia	2004 – 2005 [81] Pfizer 84240	1 g AZ and 600 mg CQ days 0, 1, 2 plus placebo SP day 0	13	NA	30.8% (5.7 – 55.9)^‡
		500 mg AZ and 600 mg CQ days 0, 1, 2 plus placebo 500 mg AZ days 0, 1, 2 and placebo SP day 0	Arm suspended after 19 randomizations; no efficacy data reported
		SP (1.5 g/75 mg) day 0 plus placebo 1 g AZ and placebo 600 mg CQ days 0, 1, 2	10	NA	80% (55.2 – 100)
Colombia and Suriname	2004 – 2005 [130] O26-46 [81] Pfizer 84227	1 g AZ days 0, 1, 2 and 600 mg CQ days 0, 1 and 300 mg CQ day 2	112	NA	60.1% (51.7 – 68.8)^‡
		500 mg AZ and 600 mg CQ days 0, 1, 2 plus placebo 500 mg AZ days 0, 1, 2	Arm suspended: inadequate efficacy 36.4% (4/11) day-28 PCR-unadjusted
		AP (1 g/400 mg) days 0, 1, 2	113		100% (NA)
Colombia and India	2006 – 2008 [84] ASTMH 62/374 [81] Pfizer 282919	2 g AZ and 600 mg CQ days 0, 1, 2	107	NA	97.2% (94.1 – 100)^‡

*Appropriate clinical and parasitic response (ACPR).

^‡Partially PCR-adjusted.

AL: Artemether–lumefantrine (Coartem); AP: Atovaquone–proguanil; AZ: Azithromycin; CQ: Chloroquine; MQ: Mefloquine; PCR: Polymerase chain reaction; PQ: Piperaquine; SP: Sulphadoxine–pyrimethamine.

Figure 1. Pharmacokinetic elimination of 1 g azithromycin through maternal serum and myometrial, adipose and placental tissue (ng/ml/h).

Table 3. Drug interactions with chloroquine.

Drug	Type	Interaction with chloroquine	Clinical significance
Chlorpromazine	Antipsychotics	Chloroquine, SP and amodiaquine increase serum concentrations of chlorpromazine 1.7 – 4.3 times [131]	Unknown
Cimetidine	Histamine h2-receptor antagonist	Cimetidine increases serum concentration of chloroquine prolonging its half-life 48% [132]	Unknown
Codeine	Opiate	Chloroquine inhibits CYP2D6 and may theoretically interfere with bio-activation of codeine to morphine [133]	Unknown
Cyclosporine	Immunosuppressant	Cyclosporine concentrations increase up to 4.3 times when used with chloroquine [134]	Cyclosporine dosages may need to be reduced during concomitant chloroquine use
Kaolin-Pectin	Antidiarrhoeal	Kaolin–Pectin reduces the area under the plasma-chloroquine concentration–time curve by ∼ 30% [135]	Unknown
Methotrexate	Antimetabolite and antifolate	Methotrexate peak concentrations are reduced 20% and its area under the concentration–time curve is reduced 28% with concomitant chloroquine use [136]	Unknown
Praziquantel	Anthelmintic	Concomitant use of chloroquine reduces concentration–time curve of praziquantel 65% and peak concentrations 59% [109]	WHO recommends inclusion of pregnant women in deworming campaigns with 40 mg/kg praziquantel [110]

Table 4. Chloroquine pharmacokinetics and azithromycin pharmacokinetics among pregnant and non-pregnant women in Papua New Guinea.

	Chloroquine pharmacokinetic study* [112]			Azithromycin pharmacokinetic study^‡ [97]
	Pregnant women (n = 30) [95% CI]	Non-pregnant women (n = 30) [95% CI]	p	Pregnant women (n = 31) [95% CI]	Non-pregnant women (n = 29) [95% CI]	p
Parameter
CL/F (l/h)	32.0 [28.8 – 36.5]	23.9 [21.3 – 26.3]	< 0.001
CLM/F (l/h)	5.74 [5.17 – 6.55]	4.29 [3.82 – 4.72]	< 0.001
V c /F (l)	3406 [2819 – 4919]	2702 [2230 – 3535]	0.007	647 [422 – 995]	249 [157 – 363]	NS
V P2/F (l)				3888 [3708 – 4104]	3672 [3456 – 3888]	0.034
V ss /F (l)	7147 [6721 – 9638]	6707 [5843 – 7158]	0.009	8355 [7460 – 8973]	6875 [6115 – 7526]	0.002
t 1/2α (h)				0.88 [0.57 – 1.36]	0.39 [0.24 – 0.56]	< 0.001
t 1/2β (h)	266 [244 – 280]	291 [272 – 313]	< 0.001	20.7 [18.3 – 22.8]	18.8 [15.3 – 21]	NS
t 1/2γ (h)				78.2 [74 – 82.5]	77.1 [71.5 – 84.5]	NS
AUC0 – ∞	35,750 (mg · h/litre) [31,343 – 39,729]	47,892 (mg · h/litre) [43,486 – 53,746]	< 0.001	28,713 (μg h litre^−1) [25,913 – 32,942]	31,781 (μg h litre^−1) [28,736 – 38,012]	NS

*Chloroquine pharmacokinetic study: all women received 450 mg base chloroquine for 3 days plus SP-IPTp.

^‡Azithromycin pharmacokinetic study: women received either two 2 g doses azithromycin plus 450 mg base chloroquine for 3 days OR two 2 g doses azithromycin plus SP-IPTp.

AUC_{0 – ∞}: Area under the curve; CL/F: Clearance from the first compartment/bioavailability; CL_M/F: Metabolic clearance/bioavailability; NS: Not significant; t _1/2α: First distribution half-life; t _1/2β: Elimination half-life; t _1/2γ: Terminal half-life; V_c /F: Volume of distribution of the first compartment/bioavailability; V_P2 /F: Volume of distribution of the second compartment/bioavailability; V_ss /F: Volume of distribution at steady state/bioavailability.

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